Cyril Benes, PhD
Assistant Professor of Medicine
Harvard Medical School
Center for Cancer Research
The Genomics of Drug Sensitivity
Explore the Benes Lab
The Benes laboratory, also known as The Center for Molecular Therapeutics, is engaged in the design and application of personalized therapies for cancer. Targeted cancer treatments have emerged from research studies showing that the biology of cancer cells differs from that of healthy cells, and that each person’s cancer has a unique genetic signature. Our goal is to pinpoint the cancer cells’ biological weak points and then to attack those weak points with smart drugs that are specifically designed for such an attack. We use a very large collection of previously established tumor cell lines derived from many different cancers as well as newly established lines from patients treated at MGH. To better understand why some patients respond more favorably than others to therapy, we use both cancer cells and other cells found in tumors and study their interplay.
We are studying the molecular basis of response to anticancer agents.
Molecular Basis of Cancer Therapeutic Response
Clinical responses to anticancer therapeutics are often restricted to a subset of cases treated. In some instances, clear evidence is available that correlates clinical responses with specific tumor genotypes. Our goal is to identify tumor cell states that predict sensitivity to anticancer agents. To accomplish this goal, we use historically established cancer cell lines as well as cancer cells obtained from tumor biopsies and study their response to anticancer agents and their combinations using high-throughput approaches. We collaborate with multiple groups at MGH and beyond to identify new treatment options for rare cancers. We use molecular profiling at multiple levels including genetic, epigenetic and proteomic to discover the mechanistic basis of drug response and identify biomarkers predictive of response in patients.
Targeting the Tumor Microenvironment
Tumors contain fibroblasts, endothelial cells and immune cells among others. These cells and the extracellular material they produce constitute the tumor microenvironment. We study how the tumor microenvironment influences therapeutic response. In particular we culture cancer associated fibroblasts from tumor biopsies. Our living collection of Patient Derived Fibroblasts gives us insights into the functional diversity of fibroblasts in tumors, and how they influence cancer cells as well as immune cells. Through these studies we aim to design therapeutic strategies targeting the tumor as a whole by perturbing routes of communication and cooperation between the different cell types present in tumors.
Resistance to Cancer Therapies
Even for the most successful anticancer therapies, drug resistance invariably emerges and limits the impact on patient lives. The molecular mechanisms underlying acquired resistance to cancer therapeutics are not well defined but are likely to be different for each therapy and cancer. We are investigating how drug combinations could overcome resistance, and within this context, studying how changes in intracellular signaling pathways affect drug response.
We are tackling the problem of therapeutic resistance using cell lines made resistant in the laboratory or isolated from resistant tumors. Previous results have shown that these cell line models do recapitulate at least some of the mechanisms of resistance at play in patients. We interrogate combinations of a panel of clinically relevant anticancer drugs as a way to quickly identify candidate therapeutic strategies and to jumpstart mechanistic studies that will help characterize the molecular basis of acquired resistance.
Center for Molecular Therapeutics
The broad objective of this Center's research is to identify molecular genetic features of a tumor that predict responsiveness to the various small molecule targeted therapies that have either recently been developed or are in early clinical development. Some of these drugs have been found to be highly effective in inducing remissions in a fraction of treated patients, and it is becoming increasingly clear that molecular features, or "biomarkers," that correlate with drug-responsiveness can be identified in these patients. Such findings can be of great value in designing clinical trials of new cancer drugs as well as in optimizing the clinical benefit of approved drugs.
Genomics of Drug Sensitivity (GDS)
The Genomics of Drug Sensitivity (GDS) Project is part of a unique 5-year collaboration between The Cancer Genome Project at the Wellcome Trust Sanger Institute (UK) and the Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center. The Center for Molecular Therapeutics has pioneered the use of high-throughput platforms for examining the relationship between tumor cell genomics and sensitivity to anti-cancer agents. The Cancer Genome Project has led the way in the systematic analysis of cancer genomes to identify genes critical in the development of human cancers. This collaboration will develop and integrate the expertise at both sites toward the goal of identifying cancer biomarkers that can be used to identify genetically defined subsets of patients most likely to respond to targeted therapies.
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Amzallag A, Ramaswamy S, Benes CH. Statistical assessment and visualization of synergies for large-scale sparse drug combination datasets. BMC Bioinformatics. 2019 Feb 18;20(1):83.
Misale S, Fatherree JP, Cortez E, Li C, Bilton S, Timonina D, Myers DT, … Benes CH. KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition. Clinical Cancer Research 2018 Oct 16; 25(2):796–807.
Dardaei L, Wang HQ, Singh M, Fordjour P, Shaw KX, … Benes CH. SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. Nat Med. 2018 May;24(4):512-517.
Kodack DP, Farago AF, Dastur A, Held MA, Dardaei L, Friboulet L, von Flotow F, … Benes CH. Primary Patient- Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care. Cell Rep. 2017 Dec 12;21(11):3298-3309.
Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, Frias RL, Gainor JF, Amzallag A, Greninger P, Lee D, Kalsy A, Gomez-Caraballo M, Elamine L, Howe E, Hur W, Lifshits E, Robinson HE, Katayama R, Faber AC, Awad MM, Ramaswamy S, Mino-Kenudson M, Iafrate AJ, Benes CH, Engelman JA. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science. December 2014.
Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, … Benes CH. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012 Mar 28;483(7391):570-5.
Top: A collection of Patient Derived Fibroblasts (PDF) established from tumor biopsies of patients at MGH. Fibroblasts were isolated from biopsies of a diverse population of non-small cell lung cancer patients. Bottom: PDFs impact the response to Epidermal Growth Factor Tyrosine Kinase Inhibitor (EGFR TKI) through secreted factors:
cancer cells sensitive to EGFR inhibition are protected by PDFs in co-culture (top) as well as in the presence of culture media conditioned by PDFs (bottom). Cancer cells are labelled red and PDFs green.
Resources from the Genomics of Drug Sensitivity in Cancer Project
For the 9 loci used by the largest cell line repositories to confirm cell line identity.
Cyril Benes, PhDPrincipal Investigator
- Nathaniel Adams
- Eliane Cortez, PhD
- Farideh Davoudi, PhD
- Kristin Dionne
- Regina Egan
- Samar Ghorbanpoor, PhD
- Patricia Greninger
- Haichuan Hu, MD
- Eunice Kim
- Aislinn Mayfield
- Xunqin "Elizabeth" Yin