My laboratory research aims to 1) leverage phenotypic screening and functional genomics to determine novel anti-cancer mechanisms of small molecules, 2) develop new targeted therapy approaches in gastrointestinal cancer, and 3) build a comprehensive community resource for drug repurposing discovery.
- Medical Oncology
Honors & Awards
Robert L. and Mary Ellenburg Endowed Faculty Scholar, Stanford University (2022)
The 20 under 40 in BioPharma, Endpoints News (2020)
Young Physician Scientist Award, American Society for Clinical Investigation (2020)
K08 Clinical Scientist Research Career Development Award, National Cancer Institute (2018)
Next Generation Award, Broad Institute (2018)
Young Investigator Award, American Society of Clinical Oncology (2014)
Howard Hughes Medical Institute Research Fellowship, HHMI (2005)
Alexandra J. Miliotis Research Fellowship in Pediatric Oncology, Miliotis Foundation (2004)
Phi Beta Kappa, Harvard University (2003)
Thomas Temple Hoopes Prize for outstanding senior thesis, Harvard University (2003)
Board Certification: American Board of Internal Medicine, Medical Oncology (2014)
Board Certification: American Board of Internal Medicine, Hematology (2015)
Fellowship: Dana Farber Cancer Institute Hematology Oncology Fellowship (2014) MA
Board Certification: American Board of Internal Medicine, Internal Medicine (2011)
Residency: Massachusetts General Hospital Internal Medicine Residency (2011) MA
Medical Education: Harvard Medical School (2008) MA
RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.
2022; 13 (1): 3181
The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.
View details for DOI 10.1038/s41467-022-30794-7
View details for PubMedID 35676246
Copper induces cell death by targeting lipoylated TCA cycle proteins.
Science (New York, N.Y.)
2022; 375 (6586): 1254-1261
Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.
View details for DOI 10.1126/science.abf0529
View details for PubMedID 35298263
RNF43 G659fs is an oncogenic mutation in colorectal cancer and sensitizes tumor cells to PI3K/mTOR inhibition.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000680263502355
- Adenosine receptor antagonists exhibit potent and selective off-target killing of FOXA1-high cancers AMER ASSOC CANCER RESEARCH. 2020
The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K
2020; 585 (7824): 293-+
Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines3-5, we identify CR8-a cyclin-dependent kinase (CDK) inhibitor6-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.
View details for DOI 10.1038/s41586-020-2374-x
View details for Web of Science ID 000537663800004
View details for PubMedID 32494016
View details for PubMedCentralID PMC7486275
Discovering the anticancer potential of non-oncology drugs by systematic viability profiling
2020; 1 (2): 235-+
Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.
View details for DOI 10.1038/s43018-019-0018-6
View details for Web of Science ID 000608021200016
View details for PubMedID 32613204
View details for PubMedCentralID PMC7328899
Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer
CANCER IMMUNOLOGY RESEARCH
2019; 7 (8): 1230-1236
Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for β2-microglobulin (B2M), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1-resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.
View details for DOI 10.1158/2326-6066.CIR-18-0683
View details for Web of Science ID 000478015500002
View details for PubMedID 31217164
View details for PubMedCentralID PMC6679789
- Novel cell line barcoding method reveals tepoxalin as a selective drug against MDR1-high tumor cells AMER ASSOC CANCER RESEARCH. 2019
- Characterization of intratumoral heterogeneity in drug sensitivity and modeling of drug combination effects using subclonal cell populations derived from a single breast cancer cell line AMER ASSOC CANCER RESEARCH. 2019
Structure of Casein Kinase 1A as a Tool in Rational Drug Design.
WILEY. 2018: 199-200
View details for Web of Science ID 000450682700364
A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles
2017; 171 (6): 1437-+
We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.
View details for DOI 10.1016/j.cell.2017.10.049
View details for Web of Science ID 000417362700023
View details for PubMedID 29195078
Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study
GENETICS IN MEDICINE
2017; 19 (7): 787-795
Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care.One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences.At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach.The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.
View details for DOI 10.1038/gim.2016.191
View details for Web of Science ID 000405385000011
View details for PubMedID 28125075
- The Drug Repurposing Hub: a next-generation drug library and information resource NATURE MEDICINE 2017; 23 (4): 405-+
Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles
2016; 6 (7): 714-726
Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of known RAS effector pathways. By comparing gene expression changes induced upon expression of wild-type and mutant alleles, we inferred the activity of specific alleles. Because alleles found to be mutated only once in 5,338 tumors rendered cells tumorigenic, these observations underscore the value of integrating genomic information with functional studies.Experimentally inferring the functional status of cancer-associated mutations facilitates the interpretation of genomic information in cancer. Pooled in vivo screen and gene expression profiling identified functional variants and demonstrated that expression of rare variants induced tumorigenesis. Variant phenotyping through functional studies will facilitate defining key somatic events in cancer. Cancer Discov; 6(7); 714-26. ©2016 AACR.See related commentary by Cho and Collisson, p. 694This article is highlighted in the In This Issue feature, p. 681.
View details for DOI 10.1158/2159-8290.CD-16-0160
View details for Web of Science ID 000383354500023
View details for PubMedID 27147599
View details for PubMedCentralID PMC4930723
- Reference pharmacologic class analysis for Connectivity Map discovery AMER ASSOC CANCER RESEARCH. 2015
A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer
2015; 27 (3): 397-408
We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.
View details for DOI 10.1016/j.ccell.2015.02.005
View details for Web of Science ID 000350977200011
View details for PubMedID 25759024
View details for PubMedCentralID PMC4398996
Identification of AML1-ETO modulators by chemical genomics
2009; 113 (24): 6193-6205
Somatic rearrangements of transcription factors are common abnormalities in the acute leukemias. With rare exception, however, the resultant protein products have remained largely intractable as pharmacologic targets. One example is AML1-ETO, the most common translocation reported in acute myeloid leukemia (AML). To identify AML1-ETO modulators, we screened a small molecule library using a chemical genomic approach. Gene expression signatures were used as surrogates for the expression versus loss of the translocation in AML1-ETO-expressing cells. The top classes of compounds that scored in this screen were corticosteroids and dihydrofolate reductase (DHFR) inhibitors. In addition to modulating the AML1-ETO signature, both classes induced evidence of differentiation, dramatically inhibited cell viability, and ultimately induced apoptosis via on-target activity. Furthermore, AML1-ETO-expressing cell lines were exquisitely sensitive to the effects of corticosteroids on cellular viability compared with nonexpressers. The corticosteroids diminished AML1-ETO protein in AML cells in a proteasome- and glucocorticoid receptor-dependent manner. Moreover, these molecule classes demonstrated synergy in combination with standard AML chemotherapy agents and activity in an orthotopic model of AML1-ETO-positive AML. This work suggests a role for DHFR inhibitors and corticosteroids in treating patients with AML1-ETO-positive disease.
View details for DOI 10.1182/blood-2008-07-166090
View details for Web of Science ID 000267147100024
View details for PubMedID 19377049
View details for PubMedCentralID PMC2699238
- Does androgen deprivation therapy in men with prostate cancer increase cardiovascular morbidity? NATURE CLINICAL PRACTICE UROLOGY 2008; 5 (2): 80-81
Gefitinib induces myeloid differentiation of acute myeloid leukemia
2005; 106 (8): 2841-2848
Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted.
View details for DOI 10.1182/blood-2005-02-0488
View details for Web of Science ID 000232466000043
View details for PubMedID 15998836
View details for PubMedCentralID PMC1895296