Dr. Pan is a board-certified, fellowship-trained medical oncologist with the Stanford Medicine Cancer Center and a clinical associate professor in the Department of Medicine, Division of Oncology.
He diagnoses and treats various oncological conditions and specializes in the treatment of bone and soft tissue sarcoma. He creates personalized and comprehensive care plans for each patient he serves.
Dr. Pan’s research focuses include understanding how genomic alterations impact the biological behavior and prognosis of sarcomas. In his work, he identifies new targets for developing innovative therapeutics for sarcoma treatment.
He has published more than fifty papers and many abstracts and presented in many cancer and immunology conferences. His papers have been published in the Journal of Clinical Oncology, JCO Precision Oncology, Nature Review Clinical Oncology, JCO Oncology Practice, Journal of Hematology and Oncology, and other peer-reviewed journals. He has also presented to his peers at international, national, and regional meetings, including the annual meetings of the American Society of Clinical Oncology, the Chinese Society Of Clinical Oncology, and the Connective Tissue Oncology Society.
Dr. Pan is a member of the American Society of Clinical Oncology, the American Association of Immunologists, the American Association for Advancement of Science, the Society for Immunotherapy of Cancer, and the Connective Tissue Oncology Society.
- Medical Oncology
Clinical Associate Professor, Medicine - Oncology
Honors & Awards
Fellow of Lymphoma Research, Lymphoma Research Foundation of America (2000)
Research Award, Cure for Lymphoma Foundation (2001)
Merit Award, American Association of Clinical Oncology (2002)
Young Investigator Award, American Society of Clinical Oncology (2002)
Outstanding Achievement Award, The Permanente Medical Group (2010)
Sidney Garfield Award for Exceptional Contributions, The Permanente Medical Group (2012)
Asian Pacific Heritage Award, Kaiser Permanente (2013)
Outstanding Teaching and Services Award, Veterans Healthcare Administration Palo Alto Section of Oncology, Stanford University (2013)
The Morris F. Collen Research Award, The Permanente Medical Group (2023)
Boards, Advisory Committees, Professional Organizations
Editorial Board, Journal of Hematology and Oncology (2023 - Present)
Medical Education: Fujian Medical University (1984) China
MS, Peking Union Medical College, Chinese Academy of Medical Sciences, Medicine (1989)
PhD, Oregon Health Sciences University, Molecular and Cellular Biology (1994)
Residency: St Mary's Medical Center Internal Medicine Residency CA
Fellowship: Stanford University Hematology and Oncology Fellowship (2002) CA
Board Certification: American Board of Internal Medicine, Medical Oncology (2022)
Community and International Work
New Hope Chinese Cancer Care Foundation
Opportunities for Student Involvement
High-dimensional single-cell analysis unveils distinct immune signatures of peripheral blood in patients with pancreatic ductal adenocarcinoma
FRONTIERS IN ENDOCRINOLOGY
2023; 14: 1181538
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with poor response to immune checkpoint inhibitors. The mechanism of such poor response is not completely understood.We assessed T-cell receptor (TCR) repertoire and RNA expression at the single-cell level using high-dimensional sequencing of peripheral blood immune cells isolated from PDAC patients and from healthy human controls. We validated RNA-sequencing data by performing mass cytometry (CyTOF) and by measuring serum levels of multiple immune checkpoint proteins.We found that proportions of T cells (CD45+CD3+) were decreased in PDAC patients compared to healthy controls, while proportion of myeloid cells was increased. The proportion of cytotoxic CD8+ T cells and the level of cytotoxicity per cell were increased in PDAC patients, with reduced TCR clonal diversity. We also found a significantly enriched S100A9+ monocyte population and an increased level of TIM-3 expression in immune cells of peripheral blood in PDAC patients. In addition, the serum level of soluble TIM-3 (sTIM-3) was significantly higher in PDAC patients compared to the non-PDAC participants and correlated with worse survival in two independent PDAC cohorts. Moreover, sTIM-3 exhibited a valuable role in diagnosis of PDAC, with sensitivity and specificity of about 80% in the training and validation groups, respectively. We further established an integrated model by combining sTIM-3 and carbohydrate antigen 19- 9 (CA19-9), which had an area under the curve of 0.974 and 0.992 in training and validation cohorts, respectively.Our RNA-seq and proteomic results provide valuable insight for understanding the immune cell composition of peripheral blood of patients with PDAC.
View details for DOI 10.3389/fendo.2023.1181538
View details for Web of Science ID 001009019300001
View details for PubMedID 37347110
View details for PubMedCentralID PMC10281055
Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy.
International journal of molecular sciences
2023; 24 (11)
Well-differentiated/de-differentiated liposarcoma (WDLPS/DDLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS); however, treatment options remain limited. WDLPS and DDLPS both exhibit the characteristic amplification of chromosome region 12q13-15, which contains the genes CDK4 and MDM2. DDLPS exhibits higher amplification ratios of these two and carries additional genomic lesions, including the amplification of chromosome region 1p32 and chromosome region 6q23, which may explain the more aggressive biology of DDLPS. WDLPS does not respond to systemic chemotherapy and is primarily managed with local therapy, including multiple resections and debulking procedures whenever clinically feasible. In contrast, DDLPS can respond to chemotherapy drugs and drug combinations, including doxorubicin (or doxorubicin in combination with ifosfamide), gemcitabine (or gemcitabine in combination with docetaxel), trabectedin, eribulin, and pazopanib. However, the response rate is generally low, and the response duration is usually short. This review highlights the clinical trials with developmental therapeutics that have been completed or are ongoing, including CDK4/6 inhibitors, MDM2 inhibitors, and immune checkpoint inhibitors. This review will also discuss the current landscape in assessing biomarkers for identifying tumors sensitive to immune checkpoint inhibitors.
View details for DOI 10.3390/ijms24119571
View details for PubMedID 37298520
Sex- and Co-Mutation-Dependent Prognosis in Patients with SMARCA4-Mutated Malignancies.
2023; 15 (10)
Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear.This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A, STK11, and Keap1 co-mutations.Out of 9221 cases with NGS performed, 125 cases (1.4%) had a mutSMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%), STK11 (mutSTK11, 12.8%), and Keap1 (mutKeap1, 8.8%) mutations. Male patients had substantially worse OS than female patients both among the entire mutSMARCA4 cohort (HR = 1.71, [95% CI 0.92-3.18]) with a median OS of 3.0 versus 43.3 months (p < 0.001), and among the NSCLC subgroup (HR = 14.2, [95% CI 2.76-73.4]) with a median OS of 2.75 months versus un-estimable (p = 0.02). Among all patients with mutSMARCA4, mutp53 versus wtp53 (HR = 2.12, [95% CI 1.04-4.29]) and mutSTK11 versus wtSTK11 (HR = 2.59, [95% CI 0.87-7.73]) were associated with worse OS. Among the NSCLC subgroup, mutp53 versus wtp53 (HR = 0.35, [0.06-1.97]) and mutKRAS versus wtKRAS (HR = 0.04, [0.003-.45]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 5.04, [1.12-22.32]), mutSTK11 versus wtSTK11 (HR = 13.10, [95% CI 1.16-148.26]), and mutKeap1 versus wtKeap1 (HR = 5.06, [95% CI 0.89-26.61}) were associated with worse OS.In our cohort of patients with mutSMARCA4, males had substantially worse prognosis than females, while mutTP53, mutKRAS, mutCDKN2A, mutSTK11 and mutKeap1were differentially associated with prognosis among all patients and among the NSCLC subgroup. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.
View details for DOI 10.3390/cancers15102665
View details for PubMedID 37345003
View details for PubMedCentralID PMC10216441
TP53 Gain-of-Function and Non-Gain-of-Function Mutations Are Associated With Differential Prognosis in Advanced Pancreatic Ductal Adenocarcinoma.
JCO precision oncology
2023; 7: e2200570
To examine the impact of TP53 gain-of-function (GOF) and non-GOF mutations on prognosis of advanced pancreatic ductal adenocarcinoma (PDAC) among patients with KRAS, CDKN2A, and SMAD4 comutations.This cohort included patients with locally advanced, recurrent, and de novo metastatic PDAC with next-generation sequencing performed from November 2017 to May 2022. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other p53 mutations (mutp53) as non-GOF. We used Cox regression modeling to examine the association between GOF and non-GOF mutp53 and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of chemotherapy, and KRAS, CDKN2A, and SMAD4 comutations.Of 893 total eligible patients, 68.5% had tumors with mutp53, 90.1% had KRAS mutations (mutKRAS), 44.7% had CDKN2A mutations (mutCDKN2A), and 17.0% had SMAD4 mutations. Among patients with mutp53, 121 had GOF and 491 had non-GOF. GOF mutp53 was associated with worse OS than non-GOF mutp53 (hazard ratio [HR], 1.27; 95% CI, 1.02 to 1.59) and wild-type p53 (wtp53; HR, 1.24; 95% CI, 0.98 to 1.57), whereas non-GOF was not associated with worse OS than wtp53 (HR, 0.95; 95% CI, 0.80 to 1.13). In addition, mutKRAS was associated with worse OS than wild-type KRAS in patients with mutCDKN2A (HR, 1.57; 95% CI, 0.88 to 2.80) but not in patients with wild-type CDKN2A (HR, 1.03; 95% CI, 0.76 to 1.39).GOF and non-GOF mutp53 were associated with differential prognosis in advanced PDAC. The adverse effect of mutKRAS on OS appeared to be primarily driven by patients with mutCDKN2A. Our results provide new insight that could be helpful for prognostic stratification in clinical practice and for aiding future clinical trial designs.
View details for DOI 10.1200/PO.22.00570
View details for PubMedID 37163715
Pain as Initial Presenting Symptom Is Associated With Delay to Seeking Medical Attention, Higher Risk of Relapse, and Shorter Survival in Patients With Early-Stage Extremity or Trunk Synovial Sarcoma.
The Permanente journal
2022; 26 (3): 94-102
BackgroundWhether the presenting symptom of pain vs mass impacts survival of early-stage synovial sarcoma is not known. Patients and MethodsThe authors investigated patients with early-stage extremity/trunk synovial sarcoma diagnosed from 2005 to 2017 at Kaiser Permanente Northern California for associations between the presenting symptom and survival. ResultsAmong 56 patients with early-stage extremity/trunk synovial sarcoma, median disease-free survival (DFS) was 20.3 months for the pain-only group (n = 19) vs 50.5 months for the mass ± pain group (n = 37) (p = 0.004), and median overall survival (OS) was 35.7 months vs 53.9 months (p = 0.009), respectively. Median DFS was 26.9 months for the pain ± mass group (n = 32) vs 48.6 months for the mass-only group (n = 24) (p = 0.047), whereas OS was not significantly different (49.6 vs. 53.6 months, p = 0.282). Pain at presentation was associated with a higher incidence of deep tumors and a higher risk of relapse. Cox regression model adjusting for age, sex, race, tumor location, tumor size, and wait-time to seek medical attention showed that pain at presentation was associated with 3-fold worse DFS and OS. ConclusionPain at presentation was an adverse risk factor for patients with early-stage extremity/trunk synovial sarcoma.
View details for DOI 10.7812/TPP/21.199
View details for PubMedID 35939568
View details for PubMedCentralID PMC9683740
Prolonged disease control with pazopanib following radiation of primary tumor for locally advanced and metastatic soft tissue sarcoma.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680304619
Clinical benefit of imatinib in patients with relapsed tenosynovial giant cell tumor/ pigmented villonodular synovitis (TGCT/PVNS).
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680304617
TP53 gain-of-function mutations and impact on CDKN2A mutation on prognosis of pancreatic ductal adenocarcinoma.
LIPPINCOTT WILLIAMS & WILKINS. 2022: E16294
View details for Web of Science ID 000863680303354
TP53 Gain-of-Function and Non-Gain-of-Function Mutations Are Differentially Associated With Sidedness-Dependent Prognosis in Metastatic Colorectal Cancer
JOURNAL OF CLINICAL ONCOLOGY
2022; 40 (2): 171-+
To examine the association of gain-of-function (GOF) and non-gain-of-function (non-GOF) TP53 mutations with prognosis of metastatic right-sided (RCC) versus left-sided colorectal cancer (LCC).This cohort study included patients with metastatic colorectal cancer (CRC) who had next-generation sequencing performed from November 2017 to January 2021. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other mutp53 as non-GOF. We used Cox regression modeling to examine the association between GOF and non-GOF mutp53 and overall survival (OS), adjusting for age, sex, ethnicity, performance status, Charlson comorbidity index and receipt of chemotherapy.Of total 1,043 patients, 735 had tumors with mutp53 and 308 had wild-type p53 (wtp53). GOF was associated with worse OS than non-GOF mutp53 only in LCC (hazard ratio [HR] = 1.66 [95% CI, 1.20 to 2.29]), but not in RCC (HR = 0.79 [95% CI, 0.49 to 1.26]). Importantly, RCC was associated with worse OS than LCC only in the subset of patients whose CRC carried non-GOF (HR = 1.76 [95% CI, 1.30 to 2.39]), but not GOF mutp53 (HR = 0.92 [95% CI, 0.55 to 1.53]) or wtp53 (HR = 0.88 [95% CI, 0.60 to 1.28]). These associations were largely unchanged after also adjusting for RAS, BRAF, and PIK3CA mutations, and microsatellite instability-high.Poorer survival of patients with metastatic RCC versus LCC appeared to be restricted to the subset with non-GOF mutp53, whereas GOF versus non-GOF mutp53 was associated with poorer survival only among patients with LCC. This approach of collectively classifying mutp53 into GOF and non-GOF provides new insight for prognostic stratification and for understanding the mechanism of sidedness-dependent prognosis. If confirmed, future CRC clinical trials may benefit from incorporating this approach.
View details for DOI 10.1200/JCO.21.02014
View details for Web of Science ID 000747787500009
View details for PubMedID 34843402
View details for PubMedCentralID PMC8718185
Impact of a Virtual Multidisciplinary Sarcoma Case Conference on Treatment Plan and Survival in a Large Integrated Healthcare System
JCO ONCOLOGY PRACTICE
2021; 17 (11): 681-+
Quantifying the impact of a multidisciplinary cancer case conference on patient outcome and care quality remains challenging.We prospectively investigated the impact of our virtual multidisciplinary sarcoma case conference (VMSCC) on treatment plan in patients presented to the VMSCC from July to October 2020 (prospective cohort) and retrospectively in patients with metastatic or locally advanced high-grade soft-tissue sarcoma (STS) reviewed in the VMSCC in 2016 and 2017 (high-grade STS cohort). We also investigated the factors related to the nonadherence to the VMSCC-recommended plan in both cohorts.In both cohorts, approximately 28% of the patients were referred to the VMSCC for review without a treatment plan. In significantly more cases, referring physicians outside of the sarcoma group did not have a plan formulated before the VMSCC review compared with the referring physicians within the sarcoma group. In 28.2% (prospective cohort) and 19.5% (high-grade STS cohort) of the patients, VMSCC recommended a different plan. The adherence to the VMSCC-recommended plan was 87.9% and 83.1%, respectively. The causes of the nonadherence were primarily due to disease progression or patient's decision against recommended therapy. The median overall survival for the high-grade STS cohort was 26 months.VMSCC affected the treatment plan in approximately 50% of the patients in both cohorts. The median overall survival of the patients with high-grade STS reviewed by the VMSCC in our cohort is comparable with the literature.
View details for DOI 10.1200/OP.20.01078
View details for Web of Science ID 000757284900011
View details for PubMedID 33852341
- Differential impact of different TP53 gain-of-function mutations on overall survival of patients with metastatic colorectal cancer: Results from a large integrated healthcare system. LIPPINCOTT WILLIAMS & WILKINS. 2021
- Association of TP53 mutation with decreased prevalence of MSI-high, RAS and PI3KCA mutations in metastatic colorectal cancer. LIPPINCOTT WILLIAMS & WILKINS. 2021
Rapid Response of a BRCA2/TP53/PTEN-Deleted Metastatic Uterine Leiomyosarcoma to Olaparib: A Case Report.
The Permanente journal
None: Patients with metastatic uterine leiomyosarcoma (uLMS) have poor prognosis due to limited treatment options, especially when disease progresses on doxorubicin and gemcitabine-docetaxel regimens. Here we report a patient whose metastatic uLMS contains a BRCA2 deep deletion as well as TP53 and PTEN deep deletion. The patient responded rapidly to olaparib, a poly (ADP-ribose) polymerase inhibitor, after progressing on gemcitabine-docetaxel, doxorubicin, and temozolomide regimens. This case report shall be helpful to the treatment of other patients with metastatic uLMS that harbors a BRCA2 mutation or deletion.
View details for DOI 10.7812/TPP/20.251
View details for PubMedID 33970096
Fourteen-Day Gemcitabine-Docetaxel Chemotherapy Is Effective and Safer Compared to 21-Day Regimen in Patients with Advanced Soft Tissue and Bone Sarcoma
2021; 13 (8)
Gemcitabine-docetaxel (G-D) combination is an effective chemotherapy for patients with advanced soft tissue and bone sarcoma, first developed with G administered on days 1 and 8, and D on day 8 every 21 days and later modified to be administered every 14 days in 2012. The 14-day regimen has become increasingly adopted. However, its efficacy and toxicities have not been compared. We identified 161 patients with metastatic or locally advanced soft tissue and bone sarcoma treated with either a 14-day or 21-day regimen within Northern California Kaiser Permanente from 1 January 2017 to 30 July 2020 and compared the outcomes and toxicity profiles of patients treated with the either regimen. Seventy-nine (49%) and 82 (51%) patients received the 14-day and the 21-day regimen, respectively, with similar response rate (22.8% and 15.8%, p = 0.26), median progression-free survival (PFS, 4.0 and 3.2 months, p = 0.15), and median overall survival (OS, 12.6 and 14.7 months, p = 0.55). Subset analysis of the untreated patients (approximately 60% of the entire cohort) as well as the patients with leiomyosarcoma only (approximately 50% of the entire cohort) showed that OS was not significantly different between the two regimens. Febrile neutropenia requiring hospitalization occurred in 10 and one patients (p = 0.006) and intolerance leading to discontinuation of chemotherapy occurred in 12 and two patients (p = 0.006) treated with the 21-day and the 14-day regimens, respectively. CDKN2A deletion/mutation or CDK4 amplification was associated with worse median OS (p = 0.06), while a RB1 deletion/mutation was associated with better median PFS (p = 0.05), and these two genomic alterations were mutually exclusive. Our data demonstrate that, compared to the traditional 21-day G-D regimen, the 14-day G-D regimen is equally effective but safer. In addition, CDKN2A and RB1 pathways play significant role on the outcomes of the patients.
View details for DOI 10.3390/cancers13081983
View details for Web of Science ID 000644016300001
View details for PubMedID 33924080
Complete Regression of Rhabdomyosarcoma in an Adult Secondary to Postoperative Wound Infection Following Limb Salvage Surgery: A Case Report.
The Permanente journal
2020; 25: 1
A 33-year old man presented with a 25-cm lower extremity embryonal rhabdomyosarcoma with presumed extensive nodal metastasis on positron emission topography scan. Neoadjuvant chemotherapy and radiation provided minimal response. Following limb salvage resection and flap coverage, a prolonged postoperative infection occurred requiring intravenous antibiotics and wound care over 5 months. Given the infection, no postoperative radiation or chemotherapy was administered. Eight months following surgery, positron emission topography scan showed complete regression of local and nodal disease. The patient has remained in complete remission for more than 4 years.Postoperative wound infection leading to complete regression of embryonal rhabdomyosarcoma has not been reported. Stimulation of the innate and adaptive immune system through infectious elements is an area of ongoing immunotherapy research to improve sarcoma treatment outcomes.
View details for DOI 10.7812/TPP/20.172
View details for PubMedID 33635775
View details for PubMedCentralID PMC8817904
Feasibility and Value of Establishing a Community-Based Virtual Multidisciplinary Sarcoma Case Conference.
JCO oncology practice
Management of soft tissue and bone sarcoma presents many challenges, both diagnostically and therapeutically, and requires multidisciplinary collaboration; however, such collaboration is often challenging to establish, especially in the community setting. We share our experiences of a virtual multidisciplinary sarcoma case conference (VMSCC).We conducted retrospective review of the VMSCC data-initially via Webex, now Microsoft Teams-and the surveys of referring physicians to understand the feasibility and value of the VMSCC.The VMSCC was established in March 2013 in Kaiser Permanente Northern California with consistent participation of the Departments of Musculoskeletal Oncology (orthopedic oncology), Musculoskeletal Radiology, Pathology, Medical Oncology, Radiation Oncology, Nuclear Medicine, Surgical Oncology, and Genetics. Pediatric Oncology participated ad hoc when pediatric sarcoma cases were presented. Referrals were from multiple specialties and regions, including the Kaiser Permanente Mid-Atlantic and Hawaii regions. From March 2013 to December 2019, 1,585 cases were reviewed encompassing 36 histologic types. More than 300 cases were reviewed per year from 2017 to 2019. Survey results of referring physicians demonstrate that the VMSCC enhanced the confidence of treating physicians, and its recommendations frequently led to treatment changes.Establishing a valuable community-based VMSCC is feasible. VMSCC recommendations frequently led to treatment changes and improved the confidence of treating physicians.
View details for DOI 10.1200/OP.20.00110
View details for PubMedID 32530806
Prevalence of delay to seeking medical attention in patients with synovial sarcoma and association with inferior outcomes.
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000560368308412
The impact of tumor NGS testing on hereditary cancer risk assessment and population management in an integrated community health care system.
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000560368301040
Implementing a genomic oncology program in an integrated health care network with large scale genomic Next Generation Sequencing (NGS) testing of advanced cancers in a community setting.
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000560368307141
Single-cell RNA sequencing reveals compartmental remodeling of tumor-infiltrating immune cells induced by anti-CD47 targeting in pancreatic cancer
JOURNAL OF HEMATOLOGY & ONCOLOGY
2019; 12 (1): 124
Human pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint inhibitor (ICPi). While the mechanism is not completely clear, it has been recognized that tumor microenvironment (TME) plays key roles. We investigated if targeting CD47 with a monoclonal antibody could enhance the response of PDAC to ICPi by altering the TME.Using immunohistochemistry, we examined tumor-infiltrating CD68+ pan-macrophages (CD68+ M) and CD163+ M2 macrophages (CD163+ M2) and tumor expression of CD47 and PD-L1 proteins in 106 cases of PDAC. The efficacy of CD47 blockade was examined in xenograft models. CD45+ immune cells from syngeneic tumor models were subjected to single-cell RNA-sequencing (scRNA-seq) by using the 10x Genomics pipeline.We found that CD47 expression correlated with the level of CD68+ M but not CD163+ M2. High levels of tumor-infiltrating CD68+ M, CD163+ M2, and CD47 expression were significantly associated with worse survival. CD47high/CD68+ Mhigh and CD47high/CD163+ M2high correlated significantly with shorter survival, whereas CD47low/CD68+ Mlow and CD47low/CD163+ M2low correlated with longer survival. Intriguingly, CD47 blockade decreased the tumor burden in the Panc02 but not in the MPC-83 syngeneic mouse model. Using scRNA-seq, we showed that anti-CD47 treatment significantly remodeled the intratumoral lymphocyte and macrophage compartments in Panc02 tumor-bearing mice by increasing the pro-inflammatory macrophages that exhibit anti-tumor function, while reducing the anti-inflammatory macrophages. Moreover, CD47 blockade not only increased the number of intratumoral CD8+ T cells, but also remodeled the T cell cluster toward a more activated one. Further, combination therapy targeting both CD47 and PD-L1 resulted in synergistic inhibition of PDAC growth in the MPC-83 but not in Panc02 model. MPC-83 but not Panc02 mice treated with both anti-CD47 and anti-PD-L1 showed increased number of PD-1+CD8+ T cells and enhanced expression of key immune activating genes.Our data indicate that CD47 targeting induces compartmental remodeling of tumor-infiltrating immune cells of the TME in PDAC. Different PDAC mouse models exhibited differential response to the anti-CD47 and anti-PD-L1 blockade due to the differential effect of this combination treatment on the infiltrating immune cells and key immune activating genes in the TME established by the different PDAC cell lines.
View details for DOI 10.1186/s13045-019-0822-6
View details for Web of Science ID 000501216300002
View details for PubMedID 31771616
View details for PubMedCentralID PMC6880569
- Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib ANTI-CANCER DRUGS 2019; 30 (5): 537–41
Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1
2019; 8 (5): e1581529
Human pancreatic ductal adenocarcinoma (PDAC) exhibits marginal responses to anti-PD-1/PD-L1 immunotherapy and its mechanism remains poorly understood. We have investigated the effect of anti-PD-L1 and c-Myc inhibition in PDAC. Using 87 patients with PDAC from our hospital database we found a significant correlation between the expression of PD-L1 and c-Myc. Moreover, the expression of both PD-L1 and c-Myc was associated with poor overall survival. In addition, we confirmed this finding with the PDAC patients in the TCGA database. Using several PDAC cell lines we demonstrated a significant correlation between the expression of PD-L1 and c-Myc. We also found that expression of PD-L1 correlated with high-grade histology. JQ1, an inhibitor of c-Myc inhibited PD-L1 expression and tumor growth. Using xenograft models, we demonstrated that the combination of JQ1 and anti-PD-L1 antibody exerted synergistic inhibition of PDAC growth. Our data demonstrated that the expression of PD-L1 and c-Myc may be helpful prognostic biomarkers, and their inhibition may potentially serve as an effective treatment for PDAC.
View details for DOI 10.1080/2162402X.2019.1581529
View details for Web of Science ID 000463705600003
View details for PubMedID 31069140
View details for PubMedCentralID PMC6492971
- Germline BRCA1 Deletion as Driver Mutation for Metastatic Urachal Adenocarcinoma in Patient Who Achieved Complete Response to Rucaparib. Journal of oncology practice 2019; 15 (5): 293-295
Real-World Experiences with Pazopanib in Patients with Advanced Soft Tissue and Bone Sarcoma in Northern California.
Medical sciences (Basel, Switzerland)
2019; 7 (3)
Background: Pazopanib was approved for advanced soft tissue sarcoma as a second- or third-line therapy based on the clinical trial "Pazopanib for metastatic soft-tissue sarcoma" (PALETTE). We hypothesized that the real-world experiences may be significantly different from the clinical trial results. Methods: We analyzed the response pattern of patients with advanced soft tissue and bone sarcoma who received pazopanib treatment between 1 January 2011 and 31 October 2018 in Kaiser Permanente Northern California. Results: A total of 123 patients with 23 different histologic subtypes were assessable. One patient with low-grade fibromyxoid sarcoma obtained complete response (CR) after 2 months of treatment with pazopanib, 12 patients (9.7%) obtained partial response (PR), 34 patients (27.6%) had stable disease (SD), while 76 patients (61.8%) developed progressive disease (PD). The disease control rate (DCR) was 46.3% (CR + PR + SD). Among the 12 patients with PR, 3 had undifferentiated pleomorphic sarcoma (UPS), 4 had leiomyosarcoma (LMS), 2 had pleomorphic rhabdomyosarcoma, 1 had pleomorphic liposarcoma, 1 had dedifferentiated liposarcoma, and 1 had angiosarcoma. The median duration of response was 9 months. Two patients with Ewing's sarcoma had SD for 6 and 13 months, and two patients with osteosarcoma had SD for 6 and 9 months. Among 65 patients assessed at 8 weeks, 9 had a response, and 10 had SD. Among 104 patients assessed at 12 weeks, 12 had a response, and 26 had SD. The median progression-free survival (PFS) was approximately 3 months for all 123 cases and for patients with UPS and LMS. Conclusions: Our cohort of patients with advanced soft tissue and bone sarcoma in Northern California treated with pazopanib had diverse histologic subtypes. The response rate (CR + PR) was higher than that of the PALETTE trial, while the DCR and the median PFS were significantly lower. The observation of PR in two patients with liposarcoma and durable SD in several patients with bone sarcoma indicates that pazopanib has activity in liposarcoma and bone sarcoma.
View details for DOI 10.3390/medsci7030048
View details for PubMedID 30889920
View details for PubMedCentralID PMC6473235
Mechanisms of Primary and Secondary Resistance to Immune Checkpoint Inhibitors in Cancer.
Medical sciences (Basel, Switzerland)
2019; 7 (2)
Immune checkpoint inhibitors (ICPis) have revolutionized cancer therapy with broad activities against a wide range of malignancies. However, in many malignancies their efficacy remains limited due to the primary resistance. Furthermore, a high percentage of patients develop progression due to the secondary resistance even after obtaining a response or achieving a stable disease. In this review, we will discuss the mechanisms that underlie the primary and secondary resistance to ICPis in cancer immunotherapy and provide an overview to impart a broad understanding of the critical issues that are encountered in clinical oncology practice.
View details for DOI 10.3390/medsci7020014
View details for PubMedID 30678257
View details for PubMedCentralID PMC6410194
WIPF1 antagonizes the tumor suppressive effect of miR-141/200c and is associated with poor survival in patients with PDAC
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
2018; 37: 167
Aberrant expression of Wiskott-Aldrich syndrome protein interacting protein family member 1 (WIPF1) contributes to the invasion and metastasis of several malignancies. However, the role of WIPF1 in human pancreatic ductal adenocarcinoma (PDAC) remains poorly understood.Human pancreatic cancer samples from PDAC patients were collected for methylation analysis. Bioinformatic prediction program and luciferase reporter assay were used to identify microRNAs regulating WIPF1 expression. The association between WIPF1 expression and the overall survival (OS) of patients with PDAC was evaluated by using The Cancer Genome Atlas (TCGA) database. The roles of miR-141/200c and WIPF1 on the invasion and metastasis of PDAC cells were investigated both in vitro and in vivo.We found that compared to the surrounding non-cancerous tissues, there was significantly increased methylation of miR-200c and miR-141 in human PDAC tissues that resulted in their silencing, whereas the members of the other cluster of miR-200 family including miR-200a, miR-200b and miR-429 were hypomethylated. Our data show that forced expression of miR-141 or miR-200c suppressed invasion and metastasis of PDAC cells both in vitro and in xenograft and identified WIPF1 as a direct target of miR-141 and miR-200c. Both miR-141 and miR-200c inhibit WIPF1 by directly interacting with its 3'-untranslated region. Remarkably, silencing of WIPF1 blocked PDAC growth and metastasis both in vitro and in vivo, whereas forced WIPF1 overexpression antagonized the tumor suppressive effect of miR-141/200c. Additionally, by using TCGA database we showed that high expression of WIPF1 correlated with poor survival in patients with PDAC. Moreover, we show that miR-141 and miR-200c blocked YAP/TAZ expression by suppressing WIPF1.We have identified WIPF1 as an oncoprotein in PDAC and a direct target of miR-141/miR-200c. We have also defined the miR-141/200c-WIPF1-YAP/TAZ as a novel signaling pathway that is involved in the regulation of the invasion and metastasis of human PDAC cells.
View details for DOI 10.1186/s13046-018-0848-6
View details for Web of Science ID 000439690300004
View details for PubMedID 30041660
View details for PubMedCentralID PMC6056910
Association of Inflammatory Markers with Disease Progression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.
The Permanente journal
2018; 22: 17-149
We investigated the effect of inflammatory biomarkers (neutrophil, platelet, and lymphocyte counts) on risk of progression in patients with metastatic melanoma treated with an immune checkpoint inhibitor targeting programmed cell death protein-1 (PD-1).This retrospective cohort study included 108 patients with malignant melanoma treated with an anti-PD-1 checkpoint inhibitor from August 2014 through December 2015. The outcome was disease progression noted on imaging or clinical examination. Follow-up began on the date of initiation of anti-PD-1 therapy and ended on the date of progression, disenrollment, death of causes other than malignant melanoma, or the end of the study in February 2017.The median time from initiating therapy with an anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts were associated with progression. The hazard ratio (HR) for neutrophil counts ≥ 5501/μL vs ≤ 3900/μL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p < 0.05). For platelet counts ≥ 304,000 vs ≤ 215,000/μL, the HR was 2.0 (CI = 1.0-3.9, p < 0.05). For lymphocyte counts ≥ 1716/μL vs ≤ 1120/μL, the HR was 0.5 (CI = 0.2-1.0, p = 0.05).For patients with metastatic melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet counts, or lower lymphocyte counts, are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.
View details for DOI 10.7812/TPP/17-149
View details for PubMedID 29616914
View details for PubMedCentralID PMC5882187
Risk Factors Including Age, Stage and Anatomic Location that Impact the Outcomes of Patients with Synovial Sarcoma.
Medical sciences (Basel, Switzerland)
2018; 6 (1)
Synovial sarcoma is a high-grade soft tissue sarcoma that inflicts mostly children and young adults with high mortality rate; however, the risk factors that impact the outcomes remain incompletely understood. We have identified the synovial sarcoma cases from the Kaiser Permanente Northern California cancer registry between 1981 and 2014. Kaplan-Meier plots were used to display disease-free survival (DFS) and overall survival (OS); log-rank tests and Cox proportional hazard models were used to determine the impact of clinical factors on DFS, OS, and disease-specific survival. Tumor size > 5.0 cm and age > 50 years were associated with higher risk of presenting with stage IV disease. Median OS for patients with stage IV was 1.3 years and 7.8 years for early-stage disease. For patients with early-stage disease, tumor size > 5.0 cm was significantly associated with worse DFS, sarcoma-specific morality, and OS. Compared to extremity primary, patients with head and neck and trunk primary had approximately three-fold higher sarcoma-specific mortality and lower OS. There was no significant difference in DFS or OS among three histologic subtypes. Pre-operative and/or post-operative chemotherapy was not associated with improvement in DFS or OS. Twenty-six patients relapsed with predominantly lung metastasis, thirteen of whom received metastatectomy with a median OS of 7.8 years, compared to 2.3 years for patients who did not receive metastatectomy. In conclusion, age older than 50 years and tumor size > 5.0 cm are risk factors for presenting with stage IV disease. For early-stage patients, trunk and head and neck primary as well as tumor size > 5.0 cm are risk factors for decreased OS.
View details for DOI 10.3390/medsci6010021
View details for PubMedID 29509716
View details for PubMedCentralID PMC5872178
Histologic Grade Is Predictive of Incidence of Epidermal Growth Factor Receptor Mutations in Metastatic Lung Adenocarcinoma.
Medical sciences (Basel, Switzerland)
2017; 5 (4)
Activating epidermal growth factor receptor (EGFR) mutations in metastatic non-small cell lung cancer (NSCLC) are associated with a high response rate to EGFR tyrosine kinase inhibitor (TKI). The current guidelines recommend routine EGFR mutational analysis prior to initiating first line systemic therapy. The clinical characteristics including smoking status, histologic type, sex and ethnicity are known to be associated with the incidence of EGFR mutations. We retrospectively analyzed 277 patients with metastatic NSCLC within Kaiser Permanente Northern California (KPNC); among these patients, 83 were positive for EGFR mutations. We performed both univariate and multivariable logistic regressions to identify predictors of EGFR mutations. We found that histologic grade was significantly associated with the incidence of EGFR mutation, regardless of ethnicity, sex and smoking status. In grade I (well differentiated) and II (moderately differentiated), histology was associated with significantly higher incidence of EGFR mutations compared to grade II-III (moderate-to-poorly differentiated) and III (poorly differentiated). Ever-smokers with grade III lung adenocarcinoma had 1.8% incidence of EGFR mutations. This study indicates that histologic grade is a predictive factor for the incidence of EGFR mutations and suggests that for patients with grade II-III or III lung adenocarcinoma, prompt initiation of first-line chemotherapy or immunotherapy is appropriate while awaiting results of EGFR mutational analysis, particularly for patients with history of smoking.
View details for DOI 10.3390/medsci5040034
View details for PubMedID 29232915
View details for PubMedCentralID PMC5753663
Oxaliplatin-Fluoropyrimidine Chemotherapy Plus Bevacizumab in Advanced Neuroendocrine Tumors: An Analysis of 2 Phase II Trials.
2016; 45 (10): 1394-1400
This study aimed to determine the safety and effectiveness of bevacizumab (B) plus FOLFOX or CAPOX in advanced neuroendocrine tumors (NETs) by performing a combined analysis of 2 separate prospective phase II studies.In the FOLFOX/B study, patients received chemotherapy without scheduled breaks in 3 cohorts: carcinoid, pancreatic NET, and poorly differentiated neuroendocrine carcinomas. In the CAPOX/B study, NET subtypes were pooled, and patients were treated with 4 cycles of CAPOX/B followed by optional maintenance therapy. Primary end points were radiographic response rate (RR) after 12 cycles (FOLFOX/B), progression-free survival (PFS) (CAPOX/B), and toxicity (both).Seventy-six patients (FOLFOX/B, n = 36; CAPOX/B, n = 40) were included. In FOLFOX/B, RR for carcinoid at 12 cycles 3/22 (13.6%), median PFS 19.3 months; RR for pancreatic NET at 12 cycles 4/12 (41.7%), median PFS 21 months; RR 1/2 (50%) in poorly differentiated neuroendocrine carcinoma; pooled RR 25% and median PFS 21 months (1-year PFS 68%). In CAPOX/B (pooled NET), RR 18% and median PFS 16.7 months (1-year PFS 65%). Predictable toxicity was observed.Neither study met its primary end point, but radiographic responses and prolonged disease stability in previously progressing patients suggest that selected patients with NET may benefit from oxaliplatin-fluoropyrimidine chemotherapy plus bevacizumab and that the combination may warrant further study.
View details for PubMedID 27171514
Understanding Teamwork in the Provision of Cancer Care: Highlighting the Role of Trust
JOURNAL OF ONCOLOGY PRACTICE
2016; 12 (11): 1084-+
Team science research has indicated that trust is a critical variable of teamwork, contributing greatly to a team's performance. Trust has long been examined in health care with research focusing on the development of trust by patients with their health care practitioners. Studies have indicated that trust is linked to patient satisfaction, adherence to treatment, continuity of care, and improved outcomes. We explore the construct of trust using a case example of a patient who received a surgical procedure for a precancerous polyp. We apply the principle of trust to the case as well as present the literature on trust and key definitions for understanding trust. Additionally, we apply the definitions presented to the specific case example by highlighting moments where trust is developed or violated. Lastly, we offer insights to health care practitioners on the development of trust in their own patient interactions to improve care.
View details for DOI 10.1200/JOP.2016.013854
View details for Web of Science ID 000392381400018
View details for PubMedID 27601505
View details for PubMedCentralID PMC5702794
- Improving care quality for patients with soft tissue and bone sarcoma by establishing a national virtual tumor board and electronic consultation platform. AMER SOC CLINICAL ONCOLOGY. 2016
Study of Arsenic Sulfide in Solid Tumor Cells Reveals Regulation of Nuclear Factors of Activated T-cells by PML and p53
2016; 6: 19793
Arsenic sulfide (AS) has excellent cytotoxic activity in acute promyelocytic leukemia (APL) but its activity in solid tumors remains to be explored. Here we show that AS and cyclosporine A (CsA) exerted synergistic inhibitory effect on cell growth and c-Myc expression in HCT116 cells. AS inhibited the expression of PML, c-Myc, NFATc1, NFATc3, and NFATc4, while stimulating the expression of p53 and NFATc2. Knockdown of PML reduced NFATc1, NFATc2, NFATc3 and NFATc4 expression while overexpression of p53 stimulated NFATc2-luciferase activity that was further augmented by AS by binding to a set of p53 responsive elements (PREs) on the NFATc2 promoter. Additionally, overexpression of p53 suppressed NFATc3 and NFATc4. Reciprocally, NFATc3 knockdown enhanced p53 while reducing MDM2 expression indicating that NFATc3 is a negative regulator of p53 while a positive regulator of MDM2, consistent with its tumor-promoting property as knockdown of NFATc3 retarded cell growth in vitro and tumor growth in xenograft. In patients with colon cancer, tumor expression of NFATc2 correlated with superior survival, while nuclear NFATc1 with inferior survival. These results indicate that AS differentially regulates NFAT pathway through PML and p53 and reveal an intricate reciprocal regulatory relationship between NFAT proteins and p53 pathway.
View details for DOI 10.1038/srep19793
View details for Web of Science ID 000368661500001
View details for PubMedID 26795951
View details for PubMedCentralID PMC4726130
Arsenic sulfide combined with JQ1, chemotherapy agents, or celecoxib inhibit gastric and colon cancer cell growth
DRUG DESIGN DEVELOPMENT AND THERAPY
2015; 9: 5851-5861
Arsenic compounds have modest cytotoxic activity in solid tumors. We investigated if arsenic sulfide (As4S4) in combination with other distinct agents could enhance its cytotoxic activity.We used gastric and colon cancer cell lines to study the synergistic effect of As4S4 in combination with BRD4 inhibitor JQ1, or with chemotherapy drug cisplatin and irinotecan or with COX2 inhibitor celecoxib. We investigated the mechanism of the cytotoxic effect of these novel combinations.We found that when As4S4 was combined with JQ1, cisplatin, irinotecan or celecoxib, its cytotoxic activity was dramatically enhanced in both gastric and colon cancer cell lines. As4S4 and JQ1 inhibited BRD4 and c-Myc while activating p53 expression synergistically. As4S4 inhibited COX2 and cyclin D1 expression. When As4S4 was combined with chemotherapy drug cisplatin or COX2 inhibitor celecoxib, its inhibition of COX2, BCL2, and p38 expression was enhanced. As4S4 and cisplatin synergistically stimulated p53, phosphor-p38 (p-p38), and increased cleaved caspase 3 (c-caspase 3).As4S4 in combination with JQ1, cisplatin, irinotecan or celecoxib showed enhanced cytotoxic effect on gastric and colon cancer cells, indicating the potential application of these novel drug combinations as part of treatment strategy that warrants further investigation. As4S4 and JQ1 demonstrate synergistic activation of p53 and inhibition of c-Myc. As4S4 and cisplatin and celecoxib activated multiple apoptosis pathways.
View details for DOI 10.2147/DDDT.S92943
View details for Web of Science ID 000363770400001
View details for PubMedID 26586936
View details for PubMedCentralID PMC4634829
Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms
2014; 33 (14): 1840-1849
NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1(+) and NFATc1(-) cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy.
View details for DOI 10.1038/onc.2013.132
View details for Web of Science ID 000334345500010
View details for PubMedID 23624921
View details for PubMedCentralID PMC3770739
Efficacy and Safety Profile of Combining Vandetanib with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer: A Meta-Analysis
2013; 8 (7): e67929
To evaluate the efficacy and safety profile of combining vandetanib with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts, ESMO Abstracts, Wanfang Database, CNKI were searched. Eligible studies were the randomized clinical trials (RCTs) that compared the efficacy and safety profile of adding vandetanib to chemotherapy with single chemotherapy in patients with advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. All meta-analysis were performed using Review Manager 5.1. The fixed-effect model weighted by the Mantel-Haenszel method was used. When considerable heterogeneity was found (p<0.1, or I(2)>50%), further analysis (subgroup analysis, sensitivity analysis or random-effect model) was performed to identify potential cause.Results reported from 5 RCTs involving 2284 patients were included in the analysis. Compared to chemotherapy alone, the addition of vandetanib resulted in a significant longer PFS (HR 0.79 [0.72-0.87], p<0.00001) and a higher ORR (RR 1.75 [1.43-2.15], p<0.00001), but failed to show advantage on OS (HR 0.96 [0.87-1.06], p = 0.44).Vandetanib has activity in NSCLC. Identification of predictive biomarkers is warranted in future trials to select a subset of patients with advanced NSCLC who may benefit from vandetanib.
View details for DOI 10.1371/journal.pone.0067929
View details for Web of Science ID 000323350700063
View details for PubMedID 23861835
View details for PubMedCentralID PMC3701636
Efficacy and safety profile of combining agents against epidermal growth factor receptor or vascular endothelium growth factor receptor with gemcitabine-based chemotherapy in patients with advanced pancreatic cancer: A meta-analysis
2013; 13 (4): 415-422
Several clinical trials have been published on gemcitabine-based chemotherapy with or without addition of agents against epidermal growth factor receptor (EGFR) or vascular endothelium growth factor receptor (VEGFR) in patients with advanced pancreatic cancer, however, with diverse results. The objective of this study was to perform a meta-analysis of the published trials.The database of CENTRAL, MEDLINE and EMBASE were searched. Eligible studies were randomized clinical trials (RCTs) that evaluated the efficacy and safety profile of adding targeted agents against EGFR or VEGFR to gemcitabine-based chemotherapy in patients with advanced pancreatic cancer. The primary outcome was overall survival (OS) while secondary outcomes included progression free survival (PFS) and overall response rate (ORR). Toxicity profiles were also assessed. Review Manager 5.1 was used to perform the analysis.Results reported from 6 RCTs involving 2733 patients were included in the analysis. Compared to gemcitabine-based chemotherapy alone, addition of an agent against EGFR resulted in significant longer OS [Hazard ratios (HR) 0.89 (0.79-0.99), p = 0.04] and longer PFS [HR 0.87 (0.79-0.97), p = 0.01], but no significant difference in ORR [RR 1.18 (0.82-1.70), p = 0.36]. The addition of an agent against VEGFR resulted in higher ORR [RR 1.54 (1.03-2.30), p = 0.04], but no advantage in OS [HR 0.95 (0.83-1.09), p = 0.47] or PFS [HR 0.97 (0.77-1.23), p = 0.82].Addition of an agent against EGFR to gemcitabine-based chemotherapy improved OS compared to gemcitabine-based chemotherapy alone in patients with advanced pancreatic cancer, while addition of an agent against VEGFR showed a modest improvement in ORR but not PFS and OS.
View details for DOI 10.1016/j.pan.2013.04.195
View details for Web of Science ID 000323464600014
View details for PubMedID 23890141
NFAT Gene Family in Inflammation and Cancer
CURRENT MOLECULAR MEDICINE
2013; 13 (4): 543-554
Calcineurin-NFAT signaling is critical for numerous aspects of vertebrate function during and after embryonic development. Initially discovered in T cells, the NFAT gene family, consisting of five members, regulates immune system, inflammatory response, angiogenesis, cardiac valve formation, myocardial development, axonal guidance, skeletal muscle development, bone homeostasis, development and metastasis of cancer, and many other biological processes. In this review we will focus on the NFAT literature relevant to the two closely related pathological systems: inflammation and cancer.
View details for Web of Science ID 000317117400007
View details for PubMedID 22950383
Brg1 governs a positive feedback circuit in the hair follicle for tissue regeneration and repair.
2013; 25 (2): 169-181
Hair follicle stem cells (bulge cells) are essential for hair regeneration and early epidermal repair after wounding. Here we show that Brg1, a key enzyme in the chromatin-remodeling machinery, is dynamically expressed in bulge cells to control tissue regeneration and repair. In mice, sonic hedgehog (Shh) signals Gli to activate Brg1 in bulge cells to begin hair regeneration, whereas Brg1 recruits NF-κB to activate Shh in matrix cells to sustain hair growth. Such reciprocal Brg1-Shh interaction is essential for hair regeneration. Moreover, Brg1 is indispensable for maintaining the bulge cell reservoir. Without Brg1, bulge cells are depleted over time, partly through the ectopic expression of the cell-cycle inhibitor p27(Kip1). Also, bulge Brg1 is activated by skin injury to facilitate early epidermal repair. Our studies demonstrate a molecular circuit that integrates chromatin remodeling (Brg1), transcriptional regulation (NF-κB, Gli), and intercellular signaling (Shh) to control bulge stem cells during tissue regeneration.
View details for DOI 10.1016/j.devcel.2013.03.015
View details for PubMedID 23602386
- Conditional NFAT activation promotes prostate oncogenesis through cell autonomous and non-cell autonomous effects AMER ASSOC CANCER RESEARCH. 2013
Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (5): 1738-1743
Development of the cerebral vessels, pharyngeal arch arteries (PAAs). and cardiac outflow tract (OFT) requires multipotent neural crest cells (NCCs) that migrate from the neural tube to target tissue destinations. Little is known about how mammalian NCC development is orchestrated by gene programming at the chromatin level, however. Here we show that Brahma-related gene 1 (Brg1), an ATPase subunit of the Brg1/Brahma-associated factor (BAF) chromatin-remodeling complex, is required in NCCs to direct cardiovascular development. Mouse embryos lacking Brg1 in NCCs display immature cerebral vessels, aberrant PAA patterning, and shortened OFT. Brg1 suppresses an apoptosis factor, Apoptosis signal-regulating kinase 1 (Ask1), and a cell cycle inhibitor, p21(cip1), to inhibit apoptosis and promote proliferation of NCCs, thereby maintaining a multipotent cell reservoir at the neural crest. Brg1 also supports Myosin heavy chain 11 (Myh11) expression to allow NCCs to develop into mature vascular smooth muscle cells of cerebral vessels. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNA-binding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Our findings reveal an important role for Brg1 and its downstream pathways in the survival, differentiation, and migration of the multipotent NCCs critical for mammalian cardiovascular development.
View details for DOI 10.1073/pnas.1218072110
View details for Web of Science ID 000314558100038
View details for PubMedID 23319608
View details for PubMedCentralID PMC3562770
- Improving detection of Lynch syndrome using a reflex immunohistochemistry algorithm for all patients with newly diagnosed colorectal cancer AMER SOC CLINICAL ONCOLOGY. 2012
- Impact of early engagement of patients with clinical trial information in a system-based multidisciplinary breast cancer clinic on clinical trial enrollment AMER SOC CLINICAL ONCOLOGY. 2012
Activation of NFAT Signaling in Podocytes Causes Glomerulosclerosis
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2010; 21 (10): 1657-1666
Mutant forms of TRPC6 can activate NFAT-dependent transcription in vitro via calcium influx and activation of calcineurin. The same TRPC6 mutants can cause FSGS, but whether this involves an NFAT-dependent mechanism is unknown. Here, we generated mice that allow conditional induction of NFATc1. Mice with NFAT activation in nascent podocytes in utero developed proteinuria and glomerulosclerosis postnatally, resembling FSGS. NFAT activation in adult mice also caused progressive proteinuria and FSGS. Ultrastructural studies revealed podocyte foot process effacement and deposition of extracellular matrix. NFAT activation did not initially affect expression of podocin, synaptopodin, and nephrin but reduced their expression as glomerular injury progressed. In contrast, we observed upregulation of Wnt6 and Fzd9 in the mutant glomeruli before the onset of significant proteinuria, suggesting a potential role for Wnt signaling in the pathogenesis of NFAT-induced podocyte injury and FSGS. These results provide in vivo evidence for the involvement of NFAT signaling in podocytes, proteinuria, and glomerulosclerosis. Furthermore, this study suggests that NFAT activation may be a key intermediate step in the pathogenesis of mutant TRPC6-mediated FSGS and that suppression of NFAT activity may contribute to the antiproteinuric effects of calcineurin inhibitors.
View details for DOI 10.1681/ASN.2009121253
View details for Web of Science ID 000282999000013
View details for PubMedID 20651158
View details for PubMedCentralID PMC3013542
- Phase II trial of 21-day regimen of irinotecan and carboplatin for chemonaive or relapsed small-cell lung cancer: Long-term survival AMER SOC CLINICAL ONCOLOGY. 2008
CNS response after erlotinib therapy in a patient with metastatic NSCLC with an EGFR mutation
NATURE CLINICAL PRACTICE ONCOLOGY
2007; 4 (10): 603-607
A 73-year-old Asian man with a history of lipidemia, hypertension and myocardial infarction presented with dizziness, decreased appetite, weight loss, nonproductive cough and fatigue. His physical performance status was good, and physical examination was unremarkable except for lower-extremity pitting edema.Physical examination, brain MRI, CT scans of the chest, abdomen and pelvis, bone scan, CT scan-guided biopsy, hematoxylin and eosin staining, EGFR mutational analysis, and chest X-ray.Stage IV non-small-cell lung cancer with brain metastasis.Oral erlotinib 150 mg daily for 10 months and ongoing, and whole-brain irradiation.
View details for DOI 10.1038/ncponc0931
View details for Web of Science ID 000249708800010
View details for PubMedID 17898810
Enhanced NFATc1 nuclear occupancy causes T cell activation independent of CD28 costimulation
JOURNAL OF IMMUNOLOGY
2007; 178 (7): 4315-4321
TCR signals induce the nuclear localization of NFATc proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases. Rapid nuclear export might allow continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling. To investigate this possibility, we analyzed mice in which T cells express a NFATc1 variant (NFATc1(nuc)) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites. NFATc1(nuc) T cells have constitutively nuclear NFATc1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro. NFATc1(nuc) T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation. These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors. In addition, NFATc1(nuc) destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines.
View details for Web of Science ID 000245197300038
View details for PubMedID 17371988
Stringent control of NFATc1 nuclear occupancy is critical for maintaining balanced immune response
GENE THERAPY AND MOLECULAR BIOLOGY
2007; 11B: 171-176
View details for Web of Science ID 000251610000008
Calcineurin/NFAT signaling in osteoblasts regulates bone mass
2006; 10 (6): 771-782
Development and repair of the vertebrate skeleton requires the precise coordination of bone-forming osteoblasts and bone-resorbing osteoclasts. In diseases such as osteoporosis, bone resorption dominates over bone formation, suggesting a failure to harmonize osteoclast and osteoblast function. Here, we show that mice expressing a constitutively nuclear NFATc1 variant (NFATc1(nuc)) in osteoblasts develop high bone mass. NFATc1(nuc) mice have massive osteoblast overgrowth, enhanced osteoblast proliferation, and coordinated changes in the expression of Wnt signaling components. In contrast, viable NFATc1-deficient mice have defects in skull bone formation in addition to impaired osteoclast development. NFATc1(nuc) mice have increased osteoclastogenesis despite normal levels of RANKL and OPG, indicating that an additional NFAT-regulated mechanism influences osteoclastogenesis in vivo. Calcineurin/NFATc signaling in osteoblasts controls the expression of chemoattractants that attract monocytic osteoclast precursors, thereby coupling bone formation and bone resorption. Our results indicate that NFATc1 regulates bone mass by functioning in both osteoblasts and osteoclasts.
View details for DOI 10.1016/j.devcel.2006.04.006
View details for Web of Science ID 000238244700011
View details for PubMedID 16740479
Overexpression of EphA2 gene in invasive human breast cancer and its association with hormone receptor status.
AMER SOC CLINICAL ONCOLOGY. 2005: 857S
View details for Web of Science ID 000230326605465
Brg1, a chromatin remodeling gene, is suppressed in ER-negative breast cancer in human.
SPRINGER. 2005: S186
View details for Web of Science ID 000233407100503
cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway
1997; 89 (1): 73-82
Cyclic adenosine monophosphate (cAMP) has tissue-specific effects on growth, differentiation, and gene expression. We show here that cAMP can activate the transcription factor Elk-1 and induce neuronal differentiation of PC12 cells via its activation of the MAP kinase cascade. These cell type-specific actions of cAMP require the expression of the serine/threonine kinase B-Raf and activation of the small G protein Rap1. Rap1, activated by mutation or by the cAMP-dependent protein kinase PKA, is a selective activator of B-Raf and an inhibitor of Raf-1. Therefore, in B-Raf-expressing cells, the activation of Rap1 provides a mechanism for tissue-specific regulation of cell growth and differentiation via MAP kinase.
View details for DOI 10.1016/S0092-8674(00)80184-1
View details for Web of Science ID A1997WR68500011
View details for PubMedID 9094716
TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways
1996; 84 (2): 299-308
Tumor necrosis factor (TNF) can induce apoptosis and activate NF-kappa B through signaling cascades emanating from TNF receptor 1 (TNFR1). TRADD is a TNFR1-associated signal transducer that is involved in activating both pathways. Here we show that TRADD directly interacts with TRAF2 and FADD, signal transducers that activate NF-kappa B and induce apoptosis, respectively. A TRAF2 mutant lacking its N-terminal RING finger domain is a dominant-negative inhibitor of TNF-mediated NF-kappa B activation, but does not affect TNF-induced apoptosis. Conversely, a FADD mutant lacking its N-terminal 79 amino acids is a dominant-negative inhibitor of TNF-induced apoptosis, but does not inhibit NF-kappa B activation. Thus, these two TNFR1-TRADD signaling cascades appear to bifurcate at TRADD.
View details for DOI 10.1016/S0092-8674(00)80984-8
View details for Web of Science ID A1996TR59500016
View details for PubMedID 8565075
Sequence, genomic organization, and chromosome localization of the mouse TRADD gene
JOURNAL OF INFLAMMATION
1996; 46 (3): 168-175
Signals triggered by tumor necrosis factor (TNF) are mediated by its two receptors: the 55 kDa TNF receptor one (TNF-R1) and the 75 kDa TNF receptor two (TNF-R2). Activation of TNF-R1 induces cell death, NF-kappa B activation, inflammatory response and anti-viral activity, while TNF-R2 mainly stimulates cell proliferation and NF-kappa B activation. The TNF-R2-associated factor TRAF2 has been shown to mediate activation of NF-kappa B by TNF-R2 and CD40. The human TNF-R1-associated death domain protein (TRADD) induces cell death and NF-kappa B activation when overexpressed. Here we describe the cloning and gene structure of the mouse homolog of TRADD. Mouse TRADD shares 75% overall amino acid sequence identity with human TRADD, suggesting high conservation of function. Mouse TRADD specifically interacts with wild type TNF-R1 but not with a truncated mutant TNF-R1 lacking its C-terminal 20 amino acids. Like human TRADD, mouse TRADD also induces activation of NF-kappa B and cell death. The expression of TRADD in mouse embryo appears developmentally regulated. The mTRADD gene contains four exons, with the fourth exon encoding all of the death domain. The mouse TRADD gene was localized to the distal region of chromosome 8.
View details for Web of Science ID A1996VA32400005
View details for PubMedID 8844497
The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral-inhibitor of apoptosis proteins
1995; 83 (7): 1243-1252
The 75 kDa tumor necrosis factor receptor (TNFR2) transduces extracellular signals via receptor-associated cytoplasmic proteins. Two of these signal transducers, TRAF1 and TRAF2, were isolated and characterized previously. We report here the biochemical purification and subsequent molecular cloning of two novel TNFR2-associated proteins, designated c-IAP1 and c-IAP2, that are closely related mammalian members of the inhibitor of apoptosis protein (IAP) family originally identified in baculoviruses. The viral and cellular IAPs contain N-terminal baculovirus IAP repeat (BIR) motifs and a C-terminal RING finger. The c-IAPs do not directly contact TNFR2, but rather associate with TRAF1 and TRAF2 through their N-terminal BIR motif-comprising domain. The recruitment of c-IAP1 or c-IAP2 to the TNFR2 signaling complex requires a TRAF2-TRAF1 heterocomplex.
View details for DOI 10.1016/0092-8674(95)90149-3
View details for Web of Science ID A1995TM76200019
View details for PubMedID 8548810
The Wnt-1 proto-oncogene regulates MAP kinase activation by multiple growth factors in PC12 cells.
1995; 11 (10): 2005-12
PC12/Wnt-1 cells display morphological changes in response to stimulation by select growth factors but do not respond to NGF. Furthermore, stimulation by EGF can induce neuronal differentiation in these cells but not in wild type cells. We have found that in these cells, compared to wild type PC12 cells, FGF and EGF stimulation of MAP kinase activity is enhanced, while NGF stimulation of MAP kinase in diminished. Finally, in cells expressing Wnt-1, the effect of cyclic adenosine monophosphate (cAMP) on MAP kinase activation is reversed; cAMP stimulates MAP kinase in wild type PC12 cells but inhibits MAP kinase in PC12/Wnt-1 cells. These data suggest that Wnt-1 expression alters the specificity of growth factor signaling in neuronal cells.
View details for PubMedID 7478519
Cloning and expression of two structurally distinct receptor-linked protein-tyrosine phosphatases generated by RNA processing from a single gene.
The Journal of biological chemistry
1993; 268 (26): 19284-91
We describe here the first example of RNA processing generating two functional receptor-linked protein-tyrosine phosphatases (PTP) (protein-tyrosine-phosphate phosphohydrolase, EC 22.214.171.124) that are structurally distinct within their catalytic domains. Two cDNAs, PTP-P1 and PTP-PS, were isolated from rat pheochromocytoma cells, which encode two receptor-linked protein-tyrosine-phosphatases and are produced by alternative splicing and differential use of polyadenylation sites. Both cDNAs share an identical extracellular domain and a single transmembrane domain, but differ within their cytoplasmic regions: PTP-P1 contains two tandem repeated PTPase catalytic domains, whereas PTP-PS contains only the amino-terminal domain. Bacterial expression of PTPase domains of both cDNAs demonstrates that PTP-P1 and PTP-PS contain tyrosine-phosphatase activity. PTP-P1 is encoded by three transcripts of approximately 8, 6, and 4 kilobases, whereas PTP-PS is encoded by a single 4.8-kilobase transcript. PTP-P1 (6 kilobases) and PTP-PS are mainly expressed within the brain and in neuronal and endocrine cells. These data suggest that PTP-P1 and PTP-PS may be involved in neuronal function.
View details for PubMedID 8396131
DOPAMINERGIC INHIBITION OF DNA-SYNTHESIS IN PITUITARY-TUMOR CELLS IS ASSOCIATED WITH PHOSPHOTYROSINE PHOSPHATASE-ACTIVITY
JOURNAL OF BIOLOGICAL CHEMISTRY
1992; 267 (34): 24169-24172
Dopaminergic D2 receptor agonists, such as bromocriptine, are potent anti-proliferative agents in the treatment of human pituitary adenomas. We have reproduced the anti-proliferative effect of dopamine in an established pituitary cell line stably transfected with the rat D2 dopamine receptor cDNA. We found that dopaminergic inhibition of DNA synthesis parallels the stimulation of a phosphotyrosine phosphatase activity. Both actions are blocked by pertussis toxin and by the phosphotyrosine phosphatase inhibitor, vanadate. We suggest that the anti-proliferative action of dopamine is mediated, at least in part, by the dopaminergic stimulation of a phosphotyrosine phosphatase.
View details for Web of Science ID A1992KA26300006
View details for PubMedID 1360008
G-PROTEIN ACTIVATION OF A HORMONE-STIMULATED PHOSPHATASE IN HUMAN TUMOR-CELLS
1992; 256 (5060): 1215-1217
The growth-inhibiting peptide hormone somatostatin stimulates phosphotyrosine phosphatase activity in the human pancreatic cell line MIA PaCa-2. This hormonal activation was mediated by a pertussis toxin-sensitive guanosine 5'-triphosphate-binding protein (G protein) in the membranes of these cells. Activation of this G protein by somatostatin stimulated the dephosphorylation of exogenous epidermal growth factor receptor prepared from A-431 cells in vitro. This pathway may mediate the antineoplastic action of somatostatin in these cells and in human tumors and could represent a general mechanism of G protein coupling that is utilized by normal cells in the hormonal control of cell growth.
View details for DOI 10.1126/science.256.5060.1215
View details for Web of Science ID A1992HV19200040
View details for PubMedID 1350382
[Effect of low protein diet, plus essential amino acids on lipid metabolism in patients with chronic renal failure].
Zhonghua nei ke za zhi
1991; 30 (2): 69-72, 124
We investigated lipoprotein profile of 18 non-dialysis patients with CRF and 17 patients on hemodialysis, and studied effect of LPD plus EAA on lipid metabolism of 18 non-dialysis patients with CRF. The results revealed that total triglyceride, cholesterol, LDL, VLDL, and semi-quantity of ApoCII, ApoCIII were significantly increased, and HDL, ApoAI ApoAI/ApoB rate, semiquantify of ApoCI were significantly reduced in non-dialysis patients and patients on hemodialysis; VLDL and Ccr were closely negative related in non-dialysis patients. The lipid abnormalities were more severe in non-dialysis patients complicated with hypertension than without hypertension. After 6 to 10 weeks' LPD plus EAA treatment in 18 non-dialysis patients, total triglyceride, cholesterol, LDL, VLDL were significantly reduced, and HDL, ApoAI, ApoAI/ApoB were significantly increased. We conclude that it is characterized by type IV hyperlipidemia in lipid abnormalities of patients with CRF, and LPD plus EAA treatment may improve it effectively.
View details for PubMedID 1864171