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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.

2019 Grantees

AACR-Genentech NextGen Grant for Transformative Cancer Research
Mandar Deepak Muzumdar, MD

Mandar Deepak Muzumdar, MD

Assistant Professor
Yale University
New Haven, Connecticut
Defining tumor cell and host adaptations in cancer progression

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.

AACR NextGen Grant for Transformative Cancer Research
Olena Morozova Vaske, PhD

Olena Morozova Vaske, PhD

Assistant Professor
University of California at Santa Cruz
Santa Cruz, California
Evaluation of gene expression outliers in pediatric cancer models

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.

2018 Grantees

AACR-The Mark Foundation NextGen Grant for Transformative Cancer Research
Birgit Knoechel, MD, PhD

Birgit Knoechel, MD, PhD

Assistant Professor
Dana-Farber Cancer Institute
Boston, Massachusetts
Epigenetic heterogeneity as a modulator of therapeutic response in T-ALL

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.

AACR NextGen Grant for Transformative Cancer Research
Kamila Naxerova, PhD

Kamila Naxerova, PhD

Assistant Professor
Massachusetts General Hospital
Charlestown, Massachusetts
Tracing the evolutionary history of lethal melanoma metastasis

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. Dr. Naxerova will utilize polyguanine genotyping, a genetic methodology for lineage tracing in human tumor samples, to reconstruct the phylogenies of 50 metastatic melanomas. She 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. She anticipates that these results will reveal fundamental patterns in melanoma metastasis and deliver clinically actionable information.

Biography
Dr. Naxerova received her BSc in molecular biotechnology with a specialization in bioinformatics from Heidelberg University and her PhD in human biology and translational medicine from Harvard University. 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 an 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.

AACR NextGen Grant for Transformative Cancer Research
Tuomas Tammela, MD, PhD

Tuomas Tammela, MD, PhD

Assistant Member
Memorial Sloan Kettering Institute for Cancer Research
New York, New York
Targeting cellular heterogeneity in cancer

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 Professor 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 Professor 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.

2017 Grantees

Breast Cancer Research Foundation-AACR NextGen Grant for Transformative Cancer Research, in honor of Nancy E. Davidson, MD
Kivanç Birsoy, PhD

Kivanç Birsoy, PhD

Assistant Professor
The Rockefeller University
New York, New York
Dissecting the role of aspartate biosynthesis in hypoxic tumor growth

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
Dr. 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.

AACR-Takeda Oncology NextGen Grant for Transformative Cancer Research
Hani Goodarzi, PhD

Hani Goodarzi, PhD

Assistant Professor
University of California, San Francisco
San Francisco, California
The RNA structural code that drives colon cancer progression and metastasis

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 is developing 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.