AACR NextGen Grants for Transformative Cancer Research
The AACR NextGen Grants for Transformative Cancer Research represent the AACR’s flagship funding initiative to stimulate highly innovative research from young investigators. This grant mechanism is intended to promote and support creative, paradigm-shifting cancer research that may not be funded through conventional channels. It is expected that these grants will catalyze significant scientific discoveries and help talented young investigators gain scientific independence. Eligibility is limited to junior faculty who have held a tenure-eligible appointment at the rank of assistant professor for no more than three years. The proposed research must represent a highly innovative approach to a major contemporary challenge in cancer research. The research can be in any area of basic, translational, or clinical science.
- Birgit Knoechel, MD, PhD
- Kamila Naxerova, PhD
- Tuomas Tammela, MD, PhD
- Kivanç Birsoy, PhD
- Costas Andreas Lyssiotis, PhD
- Sidi Chen, PhD
- Hani Goodarzi, PhD
- Paul A. Northcott, PhD
- Andrew C. Hsieh, MD
- Sophia Y. Lunt, PhD
- Nikhil Wagle, MD
2019 Grantees
AACR-Genentech NextGen Grant for Transformative Cancer Research
Mandar Deepak Muzumdar, MD
Assistant Professor
Yale University
New Haven, Connecticut
Defining tumor cell and host adaptations in cancer progression
Scientific Statement of Research
For cancers to arise, cells must acquire the capacity for sustained proliferation while overcoming both intrinsic evolutionary constraints and constraints imposed by the host environment. These properties may be attained through the sequential acquisition of gene mutations that promote cancer initiation and progression. Yet it has become increasingly clear that mutations alone are frequently incapable of driving tumorigenesis. Leveraging genetically engineered mouse models that closely recapitulate human cancers, Dr. Muzumdar’s laboratory studies tumor cell and host adaptations that cooperate with gene mutations to facilitate early cancer progression. For this project, his team will trace genetically-defined tumor subclones at single-cell resolution to discover and functionally validate transcriptional and epigenetic adaptations fostering clonal cancer evolution. In parallel, his lab will characterize how hormonal adaptations to obesity – a major cancer risk factor – promote cancer development. Together, by defining non-mutational adaptations in cancer, these studies may afford novel strategies for furthering cancer therapy.
Biography
Dr. Muzumdar is a physician-scientist and assistant professor in the Yale Cancer Biology Institute and genetics and medicine departments at the Yale University School of Medicine. He received his AB in biochemistry from Harvard College followed by an MD from the Stanford University School of Medicine, where he worked with Dr. Liqun Luo developing mouse models for high-resolution genetic analysis. He trained in internal medicine and medical oncology at the Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital, and completed a postdoctoral fellowship in cancer biology with Dr. Tyler Jacks at the Koch Institute at MIT.
Acknowledgment of Support
The AACR-Genentech NextGen Grant provides critical funding to develop my research program as an early career investigator. With the generous support of the AACR and Genentech my laboratory will combine new analytic methods with powerful cancer models, with the goal of developing novel approaches for cancer prevention and therapy.
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AACR NextGen Grant for Transformative Cancer Research
Olena Morozova Vaske, PhD
Assistant Professor
University of California at Santa Cruz
Santa Cruz, California
Evaluation of gene expression outliers in pediatric cancer models
Scientific Statement of Research
This project will use a new bioinformatics approach (outlier analysis based on RNA sequencing), drug screening, and long-read nanopore sequencing to identify and characterize novel therapeutic targets for pediatric cancers. Given the paucity of somatic coding mutations in pediatric cancer, abnormally expressed genes may be important biomarkers of response to targeted therapies in pediatric tumors. To detect such genes, Dr. Vaske had previously developed a comparative RNA-Seq analysis approach in which a single patient’s data is compared to similar data from over 11,000 cancer patients to identify over-expressed genes (gene expression outliers). In this project Dr. Vaske will identify recurrent gene expression outliers in pediatric primary tumors and cancer models and investigate the molecular mechanisms of the aberrant expression. This work will provide an evaluation of the utility of comparative RNA-Seq analysis and build rationale for incorporating RNA-Seq-defined markers into precision medicine studies for pediatric cancer patients.
Biography
Dr. Vaske is an assistant professor of molecular, cell and developmental biology at the University of California Santa Cruz, where she holds the Colligan Presidential Chair in Pediatric Genomics. Dr. Vaske’s research focuses on translational genomics of pediatric cancers. Dr. Vaske earned her BSc in molecular biology from the University of Toronto and a PhD in pediatric cancer bioinformatics from the University of British Columbia. She completed a post-doctoral fellowship at UC Santa Cruz and a clinical molecular genetics fellowship at UC San Francisco. She is also a fellow of the Canadian College of Medical Geneticists.
Acknowledgement of Support
I am very honored to receive the prestigious AACR-NextGen Grant for Transformative Cancer Research and am deeply grateful for the support. This grant enables me to develop a molecular biology program that will evaluate findings from my bioinformatics analysis and contribute to their translation in the pediatric cancer clinic.
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2018 Grantees
AACR-The Mark Foundation NextGen Grant for Transformative Cancer Research
Birgit Knoechel, MD, PhD
Assistant Professor
Dana-Farber Cancer Institute
Boston, Massachusetts
Epigenetic heterogeneity as a modulator of therapeutic response in T-ALL
Scientific Statement of Research
Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy that
frequently relapses or becomes treatment refractory. T-ALL frequently harbor activating mutations in the NOTCH1 gene, which confer sensitivity to Notch inhibitors. Yet, the rapid development of resistance has limited the clinical success of these inhibitors. We have recently shown that resistance to Notch inhibitors in T-ALL is mediated by epigenetic state transitions. Rare drugtolerant ‘persister’ cells pre-exist in dynamic equilibrium with drug-sensitive cells and give rise to the resistant population after prolonged treatment with Notch inhibitors. These studies suggest that epigenetic intratumoral heterogeneity plays a major role in diverse treatment responses. Yet, the exact epigenetic and transcriptional state of the pre-existing persister cells remain unknown. Using novel single cell sequencing technologies, we will interrogate pre-existing transcriptional and epigenetic heterogeneity in T-ALL and investigate their role in treatment response.
Biography
Dr. Knoechel is a physician-scientist and pediatric oncologist at Dana-Farber Cancer Institute and assistant professor of pediatrics at Harvard Medical School. Her research focuses on epigenetic aberrations in pediatric malignancies. Dr. Knoechel graduated with an MD/PhD degree from Albrecht-Ludwigs-Universitaet, Freiburg, Germany. She trained in T-cell immunology with Dr. Abul Abbas and completed her pediatric residency at University of California, San Francisco. She trained in pediatric hematology/oncology at Dana-Farber Cancer Institute and Boston Children’s Hospital and as postdoctoral fellow in epigenetics with Dr. Bradley Bernstein at Massachusetts General Hospital and the Broad Institute.
Acknowledgement of Support
I am very honored to have been selected as a recipient of the AACR-NextGen Grant for
Transformative Cancer Research, and I am tremendously grateful for your support. The AACR
Next-Gen Grant will provide critical funds for our work on intratumoral epigenetic heterogeneity as the basis for diverse treatment outcome.
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AACR NextGen Grant for Transformative Cancer Research
Kamila Naxerova, PhD
Assistant Professor
Massachusetts General Hospital
Charlestown, Massachusetts
Tracing the evolutionary history of lethal melanoma metastasis
Scientific Statement of Research
Metastasis remains one of the least understood aspects of cancer progression. Are distant metastasis founders a random selection of cells from the primary tumor, or do specialized metastatic clones evolve, perhaps in regional lymph nodes? Are metastases formed late in tumor progression, by highly evolved and aggressive clones, or can they be seeded early, by less evolved tumor cells? This project will attempt to answer these questions by examining the evolutionary history of melanoma. We will utilize polyguanine genotyping, a genetic methodology for lineage tracing in human tumor samples, to reconstruct the phylogenies of 50 metastatic melanomas. We will determine how often lymphatic and distant metastases share a common clonal origin and examine important events in a tumor’s evolutionary history, such as the time point of metastasis divergence, vis-à-vis clinical outcomes. We anticipate that these results will reveal fundamental patterns in melanoma metastasis and deliver clinically actionable information.
Biography
Kamila Naxerova received her BSc in molecular biotechnology with a specialization in bioinformatics from Heidelberg University in Germany, and her PhD in human biology and translational medicine from Harvard University in Cambridge, Massachusetts. Funded by a Breakthrough Award from the U.S. Department of Defense, she completed her postdoctoral training with Dr. Stephen J. Elledge at Harvard Medical School. In March 2018, she joined the Center for Systems Biology at Massachusetts General Hospital and Harvard Medical School as assistant professor. She is interested in using computational and high-throughput experimental approaches to elucidate the evolutionary history of human cancer.
Acknowledgement of Support
The 2018 AACR NextGen Grant for Transformative Cancer Research will have a profound effect on the evolution of my laboratory. It will enable me to enter a new area of research – the biology of melanoma metastasis – and thus diversify my scientific interests early on in my career, an invaluable opportunity.
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AACR NextGen Grant for Transformative Cancer Research
Tuomas Tammela, MD, PhD
Assistant Member
Memorial Sloan Kettering Institute for Cancer Research
New York, New York
Targeting cellular heterogeneity in cancer
Statement of Scientific Research
Tumors are composed of societies of cells in which the phenotype, or state, of each tumor cell is influenced by multiple cell-autonomous and cell-extrinsic factors. The diversity of these cellular states poses a challenge for effective cancer therapies. Dr. Tammela’s group approaches this problem using a combination of sophisticated genetically engineered mouse models, single cell transcriptomics, experimental manipulation of distinct tumor cell lineages, CRISPR-mediated gene regulation, and advanced imaging techniques. Dr. Tammela’s laboratory will utilize the exceptional resources developed by collaborators at MSKCC and elsewhere, such as organoids, xenografts and sophisticated computational platforms, for the translation of their findings into new treatments for human cancer. The overarching goal of these efforts is to discover pathways that drive distinct cellular phenotypes and to develop new therapeutic concepts aimed at reducing cellular heterogeneity in tumors.
Biography
Dr. Tammela earned his MD and PhD from the University of Helsinki, Finland, where he worked in the laboratory of Prof. Kari Alitalo, studying molecular mechanisms that control blood and lymphatic vessels growth. Dr. Tammela then moved to MIT for postdoctoral training on modeling cancer and its biology with Prof. Tyler Jacks. Dr. Tammela recently joined the Sloan Kettering Institute as an assistant member in the cancer biology and genetics program. Dr. Tammela’s group studies phenotypic heterogeneity of cancer cells within tumors using genetically engineered mouse models and single-cell omics approaches.
Acknowledgement of Support
I am deeply grateful for the generous support provided by the AACR. This grant enables our laboratory to mechanistically determine the underpinnings of cellular heterogeneity in cancer. I believe that these efforts can lead to novel therapeutic concepts.
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2017 Grantees
Breast Cancer Research Foundation-AACR NextGen Grant for Transformative Cancer Research, in honor of Nancy E. Davidson, MD
Kivanç Birsoy, PhD
Assistant Professor
The Rockefeller University
New York, New York
Dissecting the role of aspartate biosynthesis in hypoxic tumor growth
Scientific Statement of Research
The impact of low oxygen on cellular metabolism extends beyond central carbon metabolism as there are at least 150 biosynthetic reactions that require molecular oxygen. We recently discovered that the critical function of oxidative metabolism to support proliferation is surprisingly not energy production but rather aspartate synthesis. Upon inhibition of the electron transport chain, the cellular aspartate concentration drops to levels that cause growth arrest, and supplementation of this single amino acid is sufficient to enable cells with defective electron transport chain activity to proliferate. As many cancer cells are frequently starved for oxygen in tumors, this result raises the possibility that aspartate levels may be limiting for tumor growth in vivo and that suppression of aspartate levels in cancer cells is a promising approach to target cancer cells. Here, we aim delineate the role of aspartate metabolism in tumors cells in vivo and its upstream regulators.
Biography
Kivanc Birsoy received his undergraduate degree in molecular genetics from Bilkent University in 2004 and his PhD from Rockefeller University in 2009, where he studied molecular genetics of obesity in the laboratory of Jeffrey Friedman. In 2010, he joined the laboratory of David Sabatini at the Whitehead Institute. There, he combined forward genetics and metabolomics approaches to understand how different cancer types rewire their metabolism to adapt nutrient deprived environments. In 2016, he joined the Rockefeller faculty as Chapman-Perelman assistant professor and head of laboratory of Metabolic Regulation and Genetics.
Acknowledgement of Support
With the generous support from AACR, we aim to gain a better understanding of cancer metabolic adaptations and reveal previously unidentified metabolic liabilities of hard-to-treat tumors.
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AACR NextGen Grant for Transformative Cancer Research
Costas Andreas Lyssiotis, PhD
Assistant Professor
University of Michigan
Ann Arbor, Michigan
Intratumoral metabolic crosstalk supports pancreatic tumor growth
Scientific Statement of Research
Pancreatic tumors are characterized by a heterogeneous cellular microenvironment, a prominent stromal reaction and deregulated metabolism. The intense stromal reaction impacts the vasculature, leading to a hypoxic and nutrient poor environment. As such, these tumors must adapt how nutrients are captured and utilized to support their metabolic needs. Recently, the Lyssiotis laboratory discovered that non-tumorigenic pancreatic stromal fibroblasts provide metabolic support for the nutrient limited cancer cells through the secretion of amino acids. The goals of this proposal are to determine the mechanisms by which metabolic crosstalk exists and then to disrupt this pathway using ex vivo co-culture systems. In addition to elucidating a novel pathway of intratumoral metabolic crosstalk and uncovering an unknown role for the stroma in PDAC, these studies may also reveal new therapeutic targets.
Biography
Costas Lyssiotis obtained his bachelor’s degree in chemistry and biochemistry from the University of Michigan in 2004 and his PhD in chemical biology from The Scripps Research Institute in 2010. Costas joined the laboratory of Lewis Cantley at Harvard Medical School to pursue postdoctoral studies where his work focused on understanding oncogene driven metabolic alterations in cancer. Dr. Lyssiotis is currently an assistant professor at the University of Michigan with appointments in the Departments of Physiology and Medicine. His lab studies the biochemical pathways and metabolic requirements that enable tumor survival and growth and how this information can be used to design targeted therapies.
Acknowledgement of Support
I am honored and extremely grateful to be the recipient of this prestigious NextGen award from the AACR. This support will provide the protected time and funds to pursue our promising research investigating the therapeutic utility of targeting pancreatic cancer metabolism.
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AACR NextGen Grant for Transformative Cancer Research
Sidi Chen, PhD
Assistant Professor
Yale University
New Haven, Connecticut
Versatile tools for autochthonous screening in liver cancer
Scientific Statement of Research
Genetically engineered mouse models provide a powerful way to study genetic mutations in tumor progression. However, recent large-scale cancer genomic studies revealed thousands of aberrations in the tumors of patients across multiple cancer types. This project’s goal is to develop a versatile platform for autochthonous modeling and high-throughput genetic screening. The initial development will focus on liver cancer, a highly lethal disease with many different mutations. This project will establish in vivo HCC induction platform using somatic gene editing to enable rapid, efficient and pathology-relevant generation of autochthounous HCC models in mice, and will demonstrate its ability for high-throughput in vivo genetic screens to identify key genes governing HCC progression and drug responses in autochthonous animal models. It is anticipated that such platform can be broadly applied to virtually all cancer types, with potentials for transforming cancer modeling, genetic screening of key factors, and pre-clinical testing of therapeutic agents.
Biography
Sidi Chen earned his PhD from The University of Chicago, and received postdoctoral trainings at MIT and the Broad Institute. He is current an assistant professor of genetics in Systems Biology Institute at Yale University. His group’s research centers on cancer systems biology, leveraging in vivo genome engineering approaches such as CRISPR-mediated cancer modeling and genetic screening to identify key regulators in cancer progression, tumor immunity, and therapeutic responses.
Acknowledgement of Support
The emerging complexity of cancer genome outpaced the ability of traditional genetic methods. My project’s goal is to develop a versatile platform to enable efficient and precise cancer modeling and high-throughput screening, which might transform our ability to identify key genes governing cancer progression and drug responses, thus accelerate therapeutic discovery. The AACR NextGen Grant support is a key to success of this project.
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AACR-Takeda Oncology NextGen Grant for Transformative Cancer Research
Hani Goodarzi, PhD
Assistant Professor
University of California, San Francisco
San Francisco, California
The RNA structural code that drives colon cancer progression and metastasis
Scientific Statement of Research
RNA molecules carry functional information in their secondary structure. These structural elements play a crucial role in post-transcriptional regulation of gene expression. Deciphering the structural information encoded in the cancer transcriptome represents a major challenge in cancer biology. To overcome this challenge, we recently introduced TEISER, a computational platform for discovering regulatory structural elements. Using this framework, we have identified a number of structural elements that are putative targets of aberrant regulatory programs in cancer. This proposal focuses on the discovery of one such pathway, mediated through a previously uncharacterized structural element, involved in colon cancer metastasis. To functionally dissect this structural element (named CASE) and to understand its role in colon cancer progression, we propose the following aims: (1) characterize CASE and its role in gene expression regulation; (2) identify the factor(s) that mediates RNA stability by binding CASE; (3) assess the clinical relevance of the CASE-mediated regulatory pathway.
Biography
Dr. Goodarzi is an assistant professor in the Departments of Biochemistry and Biophysics and Urology, and a member of the Helen Diller Family Comprehensive Cancer Center. Dr. Goodarzi was previously an Anderson Cancer Center postdoctoral fellow in the laboratory of Dr. Sohail Tavazoie at the Rockefeller University. He received his PhD in molecular biology from Princeton University in 2010. Currently, he develops systems-level experimental and computational methods to study post-transcriptional regulatory phenomena that govern cancer progression. Dr. Goodarzi has won a number of honors and awards, including the 2015 Tri-Institutional Breakout Prize and the 2015 Regional Blavatnik Award.
Acknowledgement of Support
The AACR NextGen Grant for Transformative Cancer Research provides research support at a critical juncture in my scientific career. Through this support, my lab can focus on areas of cancer research that remain largely understudied. Moreover, this recognition provides a platform for fostering collaborations with other AACR members.
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2016 Grantees
AACR NextGen Grant for Transformative Cancer Research
Paul A. Northcott, PhD
Assistant Member
St. Jude Children's Research Hospital
Memphis, Tennessee
Integrative functional genomics of recurrent childhood medulloblastoma
Cancer patients who relapse following treatment for their primary malignancy almost universally die as a result of recurrent disease. This is particularly true for patients with medulloblastoma, the most common malignant pediatric brain tumor, with only ~30 percent of children with recurrent disease living beyond five years. Although there have been considerable recent advances in medulloblastoma genomics, including the discovery of biologically and clinically relevant patient subgroups driven by distinct driver alterations, the molecular basis of medulloblastoma relapse and genetic determinants of why patients fail conventional therapy remain poorly understood. Systematic, genome-wide efforts designed to compare the genomic and transcriptional landscapes of medulloblastoma relapse to ancestral, treatment naïve primary malignancy are desperately needed in order to understand the fundamental molecular roots underlying recurrence. Dr. Northcott’s AACR NextGen Grant will effectively compare mutations, DNA copy-number alterations, and gene expression signatures found in primary medulloblastomas to their relapse counterparts in a series of ~50 meticulously annotated primary/relapse pairs isolated from St. Jude clinical trial patients. These multifaceted genomic studies will systematically identify genetic events that are primary tumor-specific, relapse-specific, or shared between primary and relapse compartments. Additionally, using a combination of ultra-deep targeted sequencing performed on bulk tumor material complemented with single-cell sequencing of fresh primary and relapse biopsies, this study will quantitatively discriminate founder mutations and copy-number alterations from those that emerge during tumor evolution and relapse. Acquisition of this detailed clonal history of primary and relapse medulloblastoma will be of immediate clinical interest in an era where molecularly targeted therapies are now being prioritized and evaluated in patients at the time of relapse. Findings stemming from these integrative genomic studies will be functionally evaluated using genetically engineered mice and patient-derived xenografts. In vitro and in vivo experiments will prioritize candidate genes and thematic pathways that appear to be enriched at relapse and generate valuable systems for testing rational targeted therapeutics in a preclinical setting. Collectively, Dr. Northcott’s AACR NextGen Grant will address essential questions related to the molecular mechanisms underlying medulloblastoma relapse, informing upcoming clinical trials for a population of childhood cancer patients currently facing an unacceptably dismal prognosis.
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AACR-Bayer NextGen Grant for Transformative Cancer Research
Andrew C. Hsieh, MD
Assistant Member
Fred Hutchinson Cancer Research Center
Seattle, Washington
The translation apparatus and mRNA dynamics in cancer
Seminal discoveries in the field of oncology have largely centered on the genomic and transcriptional alterations that drive disease initiation and progression and have dramatically impacted patient care. However, the advent of new tools have led to the revelation that mRNA translation, long thought to possess only housekeeping functions, is also a critical mediator of epithelial cancer pathogenesis at the post-transcriptional level. Dr. Hsieh previously discovered that the oncogenic PI3K-AKT-mTOR pathway is dependent on the translation initiation factor and oncogene eIF4E to synthesize protein networks that drive specific cellular programs imperative for metastasis and drug resistance. This is mediated in part by increased production of oncogenic proteins translated from select mRNAs that possess specific cis-regulatory elements. These fundamental findings may be clinically impactful in two ways, as Dr. Hsieh and others have recently reported that previously unappreciated co-translationally regulated protein products can predict future cancer behavior in patients. Furthermore, his detailed in vivo studies have also revealed that drugs that target the translation machinery, such as ATP active site inhibitors of mTOR, have significant anti-cancer efficacy.
While oncogenic protein networks represent a completely untapped biorepository with significant therapeutic potential, very little is known about the structure-function relationship between the translation apparatus and specific mRNAs hijacked in epithelial cancers. Dr. Hsieh’s lab aims to directly address this impediment to the development of innovative therapies against oncogenic protein synthesis by determining the fundamental mechanisms by which the interface between the translation machinery and mRNA is usurped by epithelial cells to drive cancer formation and drug resistance. Employing a combination of highly innovative and multidisciplinary approaches, his laboratory’s mechanistic discoveries will provide some of the first insights into a new paradigm for cancer pathogenesis that delineates the dynamic interplay between a precisely defined cancerous translation apparatus and the fate of epithelial cells towards cancer progression, which will ultimately guide the development of new prognostic biomarkers and therapeutics.
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AACR-Incyte Corporation NextGen Grant for Transformative Cancer Research
Sophia Y. Lunt, PhD
Assistant Professor
Michigan State University
East Lansing, Michigan
Deciphering metabolic rewiring in cancer
Metabolism, the process of converting nutrients into energy and building blocks of life, is distinctly abnormal in cancers. To target abnormal metabolism in cancer treatment, Dr. Lunt plans to elucidate metabolic pathways indispensable for pancreatic cancer growth and investigate their regulation. Preliminary data indicate that pancreatic cancer cells are able to proliferate despite inhibition of a metabolic pathway through unknown metabolic rewiring. Her team will investigate this metabolic rewiring and explore multiple pathway inhibition by integrating mass spectrometry-based metabolomics, genome editing, patient data, and pre-clinical models of cancer. This work will lead to development of new combinatorial treatment strategies targeting multiple metabolic pathways, providing much needed treatment options for pancreatic cancer patients.
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AACR-Takeda Oncology NextGen Grant for Transformative Cancer Research
Nikhil Wagle, MD
Assistant Professor in Medicine
Dana-Farber Cancer Institute
Boston, Massachusetts
Overcoming resistance to combined ER and CDK4/6 inhibition in breast cancer
Estrogen receptor positive (ER+) metastatic breast cancer (MBC) is the most common cause of breast cancer death, resulting in more than 20,000 deaths in the U.S each year. Though many advances have been made in the treatment of ER+ MBC using agents that target the estrogen receptor, patients invariably develop resistance to these therapies. Over the past few years, the strategy of combining agents that target the ER and novel agents called CDK4/6 inhibitors have been shown to have significant benefits in patients with ER+ MBC. In 2015, the first CDK4/6 inhibitor was approved by the FDA for the first-line treatment of ER+ MBC when given in combination with an ER targeting agent. Although combined ER and CDK4/6 inhibition yields significant clinical responses in a large fraction of patients, these tumors still develop resistance to the combination. Moreover, some patients do not benefit at all from this therapy. The mechanisms of resistance to CDK4/6 inhibitor combinations are not yet known.
The goal of Dr. Wagle’s research is to improve the understanding of resistance to CDK4/6 inhibition in ER+ MBC by characterizing tumor samples from patients who have developed resistant to these drugs. The guiding hypothesis is that resistance to this combination will involve molecular and genomic alterations in the tumor cells that result in different “cell states” that confer sensitivity or resistance to ER-inhibition, CDK4/6-inhibition, or both. Dr. Wagle will use the support from the AACR NextGen Grant for Transformative Cancer Research to perform whole exome sequencing and single cell transcriptome sequencing in tumor samples obtained from 50 patients starting treatment with CDK4/6-inhibitor-containing combination therapies, as well as corresponding resistant biopsies from patients who respond to therapy and then develop disease progression. In this way, he aims to identify genomic changes and cell states involved in intrinsic and acquired resistance. Once candidate resistance genes are identified, they will be tested in Dr. Wagle’s laboratory using breast cancer cell lines to determine the mechanisms by which they cause resistance.
Once completed, this work should help understand how ER+ MBC develops resistance to combined CDK4/6 and ER inhibition, thereby aiding the development of new biomarkers for response as well as novel therapeutic strategies for cancer patients treated with CDK4/6 inhibitors.
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