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Research at Mass General
SU2C-ACS Lung Cancer Dream Team Investigator
Cyril Benes, PhDAssistant Professor of MedicineHarvard Medical School
The Benes laboratory, 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. We are focused on developing molecular diagnostics that will reveal the best treatment course for each patient and on discovering how gene mutations in cancer can be exploited to develop new treatments.
Cyril Benes, PhDPrincipal Investigator
Genetics 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 (i.e., genotypes, gene expression) that predict sensitivity to anticancer agents. To accomplish this goal, we use high-throughput screening and expose 1,000 cell lines derived from a broad spectrum of cancers to known and potential anticancer therapeutic agents. We characterize the activity of single agents and combinations to discover therapeutic applications and biomarkers of response that could be used to select patients most likely to benefit.
The use of a very large cell line collection allows us to capture some mutational events that—although relatively rare—are very important for therapeutic response. In addition, while some patient selection strategies have proven quite successful, a wide range of variation in response to treatment exists in almost all cases. Similar to this clinical observation—and perhaps related mechanistically—our large cell line collection allows us to observe important variation in drug response within a given sensitizing genotype. For example, among BRAF-mutant cell lines which are, as a group, remarkably sensitive to BRAF inhibitors, some lines do not respond signiﬁcantly. Based on these observations, we aim to identify additional biomarkers that will permit more accurate prediction of drug response in the clinic.
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. To complement genomic guided therapeutic decisions we are developing approaches to rapidly grow cells from tumor and identify clinically relevant drugs with potential for clinical efficacy in the patients from which the cells were obtained.
In recent studies we have explored the role of cells present in the tumor together with the cancer cells. Tumor contain fibroblasts, endothelial cells and immune cells among others. We are studying the impact that the fibroblasts in the tumor have on response to therapy. We use biopsy derived fibrobalasts and cancer cells to study their relationship and understand how fribroblasts might provide cancer cells with some protection against drug treatment.
We are also approaching the problem of resistance using a very different and complementary approach. We systematically identify genes that can cause resistance to a given drug in a given context using a transposon-based genetic screen. Transposons are mobile genetic elements that can insert into a host genome—in our case, the genome of cancer cells. We use an engineered version of a transposon so we can control its mobility and identify genes with expressions that are modiﬁed by its insertion, leading to drug resistance.
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.
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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Lochmann TL, Powell KM, Ham J, Floros KV, Heisey DAR, Kurupi RIJ, Calbert ML, Ghotra MS, Greninger P, Dozmorov M, Gowda M, Souers AJ, Reynolds CP, Benes CH, Faber AC. Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma. Sci Transl Med. 2018 May 16;10(441).
Dardaei L, Wang HQ, Singh M, Fordjour P, Shaw KX, et al. SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. Nat Med. 2018 May;24(4):512-517.
Yuan TL, Amzallag A, Bagni R, Yi M, Afghani S, Burgan W, et al. Differential Effector Engagement by Oncogenic KRAS. Cell Rep. 2018 Feb 13;22(7):1889-1902.
Kodack DP, Farago AF, Dastur A, Held MA, Dardaei L, Friboulet L, von Flotow F, et al. Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care. Cell Rep. 2017 Dec 12;21(11):3298-3309.
Lapek JD Jr, Greninger P, Morris R, Amzallag A, Pruteanu-Malinici I, Benes CH, Haas W. Detection of dysregulated protein-association networks by high-throughput proteomics predicts cancer vulnerabilities. Nat Biotechnol. 2017 Oct;35(10):983-989.
Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, et al. Systematic identification ofgenomic markers of drug sensitivity in cancer cells. Nature. 2012 Mar 28;483(7391):570-5.
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