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. The research can be in any area of basic, translational, or clinical science.

2020 Grantees

Research
Using novel patient-derived organoid models of metastatic colorectal cancer, Dr. Ganesh’s group recently demonstrated that disseminating colorectal cancers (CRC) undergo a dynamic phenotypic switch from a tumor initiating cancer stem cell state to a distinct metastasis stem cell (MetSC) state that is required for metastasis initiation and therapy resistance. In this project, she is set to integrate transcriptomic and epigenetic analyses of patient samples with mechanistic dissection in cutting-edge patient-derived organoid models and orthotopic transplantation mouse models of metastatic colorectal cancer.

Biography
Dr. Ganesh received her MD/PhD from the University of Cambridge/MRC Laboratory of Molecular Biology. She trained in internal medicine at Beth Israel Deaconess Medical Center and in medical oncology at Memorial Sloan Kettering Cancer Center, where she completed a postdoctoral fellowship. Her laboratory studies mechanisms of regenerative plasticity in metastasis. A physician-scientist, she is currently an assistant member at Memorial Sloan Kettering Cancer Center in the Molecular Pharmacology Program and Gastrointestinal Oncology Service.

Acknowledgment of Support
I am deeply honored to have been selected as a 2020 AACR NextGen Grant for Transformative Cancer Research recipient. This grant will provide critical funds to enable us to pursue an ambitious program of research to better understand and treat advanced cancers.

Research
Modulation of T cell metabolism represents a promising strategy to augment responses to immunotherapy. Leveraging new methods that they’ve developed, Dr. Spitzer and his lab members will quantify metabolic adaptations along with markers of T cell differentiation and function at the single-cell level. Through parallel studies in mouse models and primary patient biospecimens, they seek to understand the metabolic requirements of T cells during tumor eradication.

Biography
Dr. Spitzer completed his graduate training in immunology at Stanford University, where he developed experimental and analytical methods to model the state of the immune system and immune responses to cancer using high dimensional single-cell data. He then moved to UCSF as a Parker Fellow and a Sandler Faculty Fellow, where he is currently an assistant professor in the Departments of Otolaryngology-Head and Neck Surgery and of Microbiology & Immunology, as well as an investigator of the Parker Institute for Cancer Immunotherapy and the Chan Zuckerberg Biohub.

Acknowledgment of Support
I am so appreciative for the support of our work through a 2020 AACR NextGen Grant for Transformative Cancer Research. This grant will provide essential funds and resources to achieve our goal of improving immunotherapy for breast cancer through a deeper understanding of T cell metabolic function.

Research
Dr. Borniger aims to investigate how mammary tumors in the periphery reshape neuronal activity across the entire brain to alter sleep/wake behavior. In addition, he aims to test the role these neuronal ensembles play in the tumor’s ability to evade the immune system and modulate systemic physiology. He is set to map how tumor development (premalignancy to malignancy and metastasis) alters brain-wide neural activity, using light-sheet tomography to visualize cFos expression and distribution throughout the entire brain in an unbiased fashion. Then, his team plans to use scRNA-seq to “trap” and transcriptionally profile activated neurons. Finally, using optogenetics they will examine how manipulation of these circuits alters the intra-tumor immune response and sleep/wake behavior.

Biography
Dr. Borniger completed a PhD in neuroscience at The Ohio State University, focusing on distal communication between breast cancer and the brain. He completed a BRAIN Initiative postdoctoral fellowship at Stanford University, where he applied cutting-edge techniques to assess neural circuit activity in mouse models of cancer. He is currently is an assistant professor with dual appointments in the neuroscience and cancer divisions at Cold Spring Harbor Laboratory.

Acknowledgment of Support
This award provides essential funding for my laboratory as an early stage investigator. This support will allow my group to tackle pressing questions regarding the basic biology of breast cancer by using a suite of systems neuroscience techniques, with the ultimate goal of identifying targets for validation or preventative therapy.

2019 Grantees

Research
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 is identifying recurrent gene expression outliers in pediatric primary tumors and cancer models and investigating the molecular mechanisms of the aberrant expression. This work can thus demonstrate the utility of comparative RNA-Seq analysis and provide rationale for incorporating RNA-Seq-defined markers into precision medicine studies for pediatric cancer patients.

Biography
Dr. Vaske earned her 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. She 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. Her research focuses on translational genomics of pediatric cancers.

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

Research
Acute T-cell lymphoblastic leukemia (T-ALL) frequently harbor activating mutations in the NOTCH1 gene, which confer sensitivity to Notch inhibitors. Dr. Knoechel’s group has previously shown that resistance to Notch inhibitors in T-ALL is mediated by epigenetic state transitions. Rare drug-tolerant “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. Using novel single cell sequencing technologies, Dr. Knoechel’s group is interrogating pre-existing transcriptional and epigenetic heterogeneity in T-ALL and investigating their role in treatment response.

Biography
Dr. Knoechel graduated with an MD/PhD degree from Albrecht-Ludwigs-Universitaet, Freiburg, Germany. She trained in T-cell immunology and completed her pediatric residency at the University of California, San Francisco. She trained in pediatric hematology/oncology at Dana-Farber Cancer Institute and Boston Children’s Hospital and as a postdoctoral fellow in epigenetics at Massachusetts General Hospital and the Broad Institute. 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.

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.

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? Dr. Naxerova is utilizing polyguanine genotyping, a genetic methodology for lineage tracing in human tumor samples, to reconstruct the phylogenies of 50 metastatic melanomas. She is determining how often lymphatic and distant metastases share a common clonal origin and examining important events in a tumor’s evolutionary history, such as the time point of metastasis divergence, vis-à-vis clinical outcomes.

Biography
Dr. Naxerova received 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 at Harvard Medical School. In 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.

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 is employing different techniques/technologies, including single cell transcriptomics, experimental manipulation of distinct tumor cell lineages, and CRISPR-mediated gene regulation, 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 studied molecular mechanisms that control blood and lymphatic vessels growth. Dr. Tammela then moved to MIT for postdoctoral training on modeling cancer and its biology. Now at the Memorial Sloan Kettering Cancer Institute, he 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

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. Dr. Birsoy’s group previously 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. In this project, he is delineating the role of aspartate metabolism in tumors cells in vivo and its upstream regulators. 

Biography
Dr. Birsoy received his PhD from Rockefeller University in 2009, where he studied molecular genetics of obesity. In 2010, he joined 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.

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.