PGY IV Resident in Radiation Oncology.
Recipient of the B. Leonard Holman Research Pathway by the American Board of Radiology
Durability of response in metastatic melanoma patients after combined treatment with radiation therapy and ipilimumab.
2020; 7 (1): MMT36
Aim: We previously reported a prospective trial evaluating the safety and efficacy of combining ipilimumab and radiation therapy in patients with metastatic melanoma. Herein, we provide a long-term update on patients with complete response (CR) or partial response (PR).Patients & methods: We continued to follow these patients with serial imaging including computed tomography, PET or MRI.Results: Two of the three patients with CR are still alive and without evidence of melanoma but with chronic treatment-induced hypophysitis. The third patient died of hepatocellular carcinoma, but with no evidence of melanoma. Among the three patients with PR, two achieved CR after pembrolizumab monotherapy.Conclusion: This long-term follow up reveals the striking durability of the CRs, which appears to correlate with a grade 2-3 hypophysitis.
View details for DOI 10.2217/mmt-2019-0020
View details for PubMedID 32399174
Predicting per-lesion local recurrence in locally advanced non-small cell lung cancer following definitive radiation therapy using pre- and mid-treatment metabolic tumor volume.
Radiation oncology (London, England)
2020; 15 (1): 114
We evaluated whether pre- and mid-treatment metabolic tumor volume (MTV) predicts per lesion local recurrence (LR) in patients treated with definitive radiation therapy (RT, dose≥60 Gy) for locally advanced non-small cell lung cancer (NSCLC).We retrospectively reviewed records of patients with stage III NSCLC treated from 2006 to 2018 with pre- and mid-RT PET-CT. We measured the MTV of treated lesions on the pre-RT (MTVpre) and mid-RT (MTVmid) PET-CT. LR was defined per lesion as recurrence within the planning target volume. Receiver operating characteristic (ROC) curves, cumulative incidence rates, and uni- and multivariable (MVA) competing risk regressions were used to evaluate the association between MTV and LR.We identified 111 patients with 387 lesions (112 lung tumors and 275 lymph nodes). Median age was 68 years, 69.4% were male, 46.8% had adenocarcinoma, 39.6% had squamous cell carcinoma, and 95.5% received concurrent chemotherapy. Median follow-up was 38.7 months. 3-year overall survival was 42.3%. 3-year cumulative incidence of LR was 26.8% per patient and 11.9% per lesion. Both MTVpre and MTVmid were predictive of LR by ROC (AUC = 0.71 and 0.76, respectively) and were significantly associated with LR on MVA (P = 0.004 and P = 7.1e-5, respectively). Among lesions at lower risk of LR based on MTVpre, higher MTVmid was associated with LR (P = 0.001).Per-lesion, larger MTVpre and MTVmid predicted for increased risk of LR. MTVmid was more highly predictive of LR than MTVpre and if validated may allow for further discrimination of high-risk lesions at mid-RT informing dose painting strategies.
View details for DOI 10.1186/s13014-020-01546-y
View details for PubMedID 32429982
FLT-PET-CT for the Detection of Disease Recurrence After Stereotactic Ablative Radiotherapy or Hyperfractionation for Thoracic Malignancy: A Prospective Pilot Study.
Frontiers in oncology
2019; 9: 467
Differentiating local recurrence from post-treatment changes on PET scans following stereotactic ablative radiotherapy (SABR) or hyperfractionation for lung tumors is challenging. We performed a prospective pilot study of 3-deoxy-3-[18F]-fluorothymidine (FLT)-PET-CT in patients with equivocal post-radiation FDG-PET-CT to assess disease recurrence. Methods: We prospectively enrolled 10 patients, 9 treated with SABR and 1 with hyperfractionated external beam radiotherapy for thoracic malignancy with subsequent equivocal follow-up FDG-PET-CT, to undergo FLT-PET-CT prior to biopsy or serial imaging. FLT-PET scans were interpreted by a radiologist with experience in reading FLT-PET-CT and blinded to the results of any subsequent biopsy or imaging. Results: Of the 10 patients enrolled, 8 were evaluable after FLT-PET-CT. Based on the FLT-PET-CT, a blinded radiologist accurately predicted disease recurrence vs. inflammatory changes in 7 patients (87.5%). The combination of higher lesion SUVmax and higher ratio of lesion SUVmax to SUVmax of mediastinal blood pool was indicative of recurrence. Qualitative assessment of increased degree of focality of the lesion also appears to be indicative of disease recurrence. Conclusion: Adjunctive FLT-PET-CT imaging can complement FDG-PET-CT scan in distinguishing post-treatment radiation changes from disease recurrence in thoracic malignancies. These findings support the investigation of FLT-PET-CT in a larger prospective study.
View details for DOI 10.3389/fonc.2019.00467
View details for PubMedID 31214507
View details for PubMedCentralID PMC6555304
Management of Metastatic Spinal Cord Compression.
Southern medical journal
2017; 110 (9): 586–93
Cancer metastasis is a key event in tumor progression associated not only with mortality but also significant morbidity. Metastatic disease can promote end-organ dysfunction and even failure through mass effect compression of various vital organs including the spinal cord. In such cases, prompt medical attention is needed to restore neurological function, relieve pain, and prevent permanent damage. The three therapeutic approaches to managing metastatic spinal cord compression include corticosteroids, surgery, and radiation therapy. Although each may improve patients' symptoms, their combination has yielded the best outcome. In cancer patients with clinical suspicion of spinal cord compression, dexamethasone should be initiated followed by surgical decompression, when possible, and radiation. The latter becomes the preferred treatment in patients with inoperable disease.
View details for DOI 10.14423/SMJ.0000000000000700
View details for PubMedID 28863223
Predictive role of PD-L1 expression in the response of renal Medullary carcinoma to PD-1 inhibition.
Journal for immunotherapy of cancer
2017; 5 (1): 62
Renal medullary carcinoma is one of the rarest malignancies arising from the kidney. Despite various aggressive therapeutic regimens, mortality remains significantly high (95%) with a median overall survival of 5 months. Furthermore, the scarcity of this malignancy renders randomized clinical trials impossible. We examined the expression of programmed death ligand 1 (PD-L1) in two new renal medullary carcinoma cases, investigated their responses to the PD-L1 inhibitor nivolumab and explored the predictive role of the rate of PD-L1 expression in such response.Two African-American patients (male and female) with sickle cell trait who presented to our center with hematuria and flank pain were diagnosed with metastatic renal medullary carcinoma. PD-L1 was expressed at rate of 25% and 60% in patient 1 and 2 respectively. Following nephrectomy, they were started on nivolumab. Patient 1 initially responded to the treatment with regression of metastatic lesions. However, following this early response, patient 1 who has been receiving nivolumab for more than 15 months, was noted to have a disease progression. Patient 2 had disease progression after 3 months of nivolumab therapy.Although PD-L1 is expressed in these patients with renal medullary carcinoma, response to nivolumab was only observed in patient 1 whose tumor has the lowest rate of PD-L1 expression. This may suggest that in RMC, response to PD-L1 inhibition therapy may not correlate with the rate of PD-L1 expression.
View details for DOI 10.1186/s40425-017-0267-9
View details for PubMedID 28807004
View details for PubMedCentralID PMC5557570
Design and structure activity relationship of tumor-homing histone deacetylase inhibitors conjugated to folic and pteroic acids.
European journal of medicinal chemistry
2015; 96: 340–59
Histone deacetylase (HDAC) inhibition has recently emerged as a novel therapeutic approach for the treatment of various pathological conditions including cancer. Currently, two HDAC inhibitors (HDACi) – Vorinostat and Romidepsin – have been approved for the treatment of cutaneous T-cell lymphoma. However, HDACi remain ineffective against solid tumors and are associated with adverse events including cardiotoxicity. Targeted delivery may enhance the therapeutic indices of HDACi and enable them to be efficacious against solid tumors. We showed herein that morphing of folic and pteroic acids into the surface recognition group of HDACi results in hydroxamate and benzamide HDACi which derived tumor homing by targeting folate receptor (FR), a receptor commonly overexpressed in solid tumors. We observed a correlation between the potency of HDAC1 inhibition and cytotoxicity as only the potent pteroate hydroxamates, 11d and 11e, displayed antiproliferative activity against two representative FR-expression cancer cells. Our observation further supports the previous results which suggest that for a drug to be successfully targeted using the FR, it must be extremely potent against its primary target as the FR has a low delivery efficiency.
View details for DOI 10.1016/j.ejmech.2015.04.014
View details for PubMedID 25899338
View details for PubMedCentralID PMC4433810
The antileishmanial activity of isoforms 6- and 8-selective histone deacetylase inhibitors.
Bioorganic & medicinal chemistry letters
2014; 24 (20): 4826–30
Histone deacetylase inhibitors (HDACi) pleiotropy is largely due to their nonselective inhibition of various cellular HDAC isoforms. Connecting inhibition of a specific isoform to biological responses and/or phenotypes is essential toward deconvoluting HDACi pleiotropy. The contribution of classes I and II HDACs to the antileishmanial activity of HDACi was investigated using the amastigote and promastigote forms of Leishmania donovani. We observed that the antileishmanial activities of HDACi are largely due to the inhibition of HDAC6-like activity. This observation could facilitate the development of HDACi as antileishmanial agents.
View details for DOI 10.1016/j.bmcl.2014.08.060
View details for PubMedID 25240614
View details for PubMedCentralID PMC4225773
Synthesis and structure-activity relationship of 3-hydroxypyridine-2-thione-based histone deacetylase inhibitors.
Journal of medicinal chemistry
2013; 56 (24): 9969–81
We previously identified 3-hydroxypyridine-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure-activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but devoid of HDAC1 inhibition. To delineate further the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds, 10d and 14e, with potent HDAC6 and HDAC8 activities that are inactive against HDAC1. These new HDACi possess anticancer activities against various cancer cell lines including Jurkat J.γ1 for which SAHA and the previously disclosed 3HPT-derived HDACi were inactive.
View details for DOI 10.1021/jm401225q
View details for PubMedID 24304348
View details for PubMedCentralID PMC4029159
3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition.
Journal of medicinal chemistry
2013; 56 (9): 3492–3506
Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines.
View details for DOI 10.1021/jm301769u
View details for PubMedID 23547652
View details for PubMedCentralID PMC3657749
Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed.
Future medicinal chemistry
2012; 4 (4): 505–24
Histone deacetylase inhibitors (HDACis) have now emerged as a powerful new class of small-molecule therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Over 490 clinical trials have been initiated in the last 10 years, culminating in the approval of two structurally distinct HDACis - SAHA (vorinostat, Zolinza™) and FK228 (romidepsin, Istodax™). However, the current HDACis have serious limitations, including ineffectively low concentrations in solid tumors and cardiac toxicity, which is hindering their progress in the clinic. Herein, we review the primary paradigms being pursued to overcome these hindrances, including HDAC isoform selectivity, localized administration, and targeting cap groups to achieve selective tissue and cell type distribution.
View details for DOI 10.4155/fmc.12.3
View details for PubMedID 22416777
View details for PubMedCentralID PMC3341130
Tamoxifen-poly(ethylene glycol)-thiol gold nanoparticle conjugates: enhanced potency and selective delivery for breast cancer treatment.
2009; 20 (12): 2247–53
The breast cancer treatment drug tamoxifen has been widely administered for more than three decades. This small molecule competes with 17beta-estradiol for binding to estrogen receptor, a hormone receptor upregulated in a majority of breast cancers, subsequently initiating programmed cell death. We have synthesized a thiol-PEGylated tamoxifen derivative that can be used to selectively target and deliver plasmonic gold nanoparticles to estrogen receptor positive breast cancer cells with up to 2.7-fold enhanced drug potency in vitro. Optical microscopy/spectroscopy, time-dependent dose-response data, and estrogen competition studies indicate that augmented activity is due to increased rates of intracellular tamoxifen transport by nanoparticle endocytosis, rather than by passive diffusion of the free drug. Both ligand- and receptor-dependent intracellular delivery of gold nanoparticles suggest that plasma membrane localized estrogen receptor alpha may facilitate selective uptake and retention of this and other therapeutic nanoparticle conjugates. Combined targeting selectivity and enhanced potency provides opportunities for both multimodal endocrine treatment strategies and adjunctive laser photothermal therapy.
View details for DOI 10.1021/bc9002212
View details for PubMedID 19919059
View details for PubMedCentralID PMC2839930