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FINDING CURES TOGETHER<sup>SM</sup>

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.  

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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