The AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grants support early- to mid-career investigators employing highly innovative approaches to major problems or challenges in cancer research. Funded projects are expected to have a potentially transformative impact on future clinical practice.

2022 Grantees

Research

Metastasis is a complex multi-step process, during which, tumor cells must profoundly alter their metabolism to adapt to the differing environments they encounter. Although metastatic seeding of specific organ sites can predict disease severity and patient prognosis, the molecular logic underlying when and to which organ a tumor cell will metastasize remains unclear. Dr Perera’s lab is set to explore the metabolic features within the primary tumor that define which secondary tissue a metastatic cell will ultimately colonize. Using innovative mouse models that enable metabolite profiling of tumor cells and their organelles, Dr Perera aims to discover master regulators that promote metastasis, and manipulate these drivers to disable the aggressive features of metastatic pancreatic ductal adenocarcinoma.   

Biography

Rushika M. Perera PhD is the recipient of the NIH Director’s New Innovator Award, the Damon Runyon-Rachleff Innovation Award, the AACR NextGen Star Award and the 2021 Gunter Blobel Early Career Award of the American Society for Cell Biology. She is currently an Associate Professor in the School of Medicine at the University of California, San Francisco. Her research program seeks to understand how metabolic organelles such as the lysosome contribute to cellular plasticity and adaptation to stress, with a focus on pancreatic cancer.

Acknowledgement of Support

The AACR-MPM Transformative Cancer Research Grant provides us with a unique opportunity to pursue a new line of research at the interface of cell biology, metabolism and cancer biology. I am incredibly grateful to the AACR and MPM for supporting our ideas and research goals.

Research

Mutant transcriptional machineries have been found to form transcriptional condensates. While wild type nucleophosmin1 (NPM1) forms liquid-liquid phase separation (LLPS) at the nucleolus, mutant NPM1 (NPM1c) moves to the cytoplasm and forms smaller puncta dots in the nucleus. Dr. Zhang and his research group uncovered a neomorphic, transcriptional-amplifier function of NPM1c on chromatin that sustains a pathogenic leukemia transcription program. With this AACR grant, they seek to use state-of-art comprehensive approaches to address the fundamental question of transcriptional dysregulation in cancer.

Biography

Dr. Xiaotian Zhang obtained his Bachelor’s degree in Biological Sciences from Fudan University in Shanghai. He obtained his Ph.D. in Molecular Human Genetics at Baylor College of Medicine. After a stint at the Van Andel Institute for a three-year special fellowship, he was appointed as a research investigator in the University of Michigan. Dr. Zhang is currently a tenure-track assistant professor in the Department of Biochemistry and Molecular Biology at the University of Texas Health Science Center at Houston.

Acknowledgement of Support

I want to thank AACR and MPM Oncology Charitable Foundation for the Transformative Cancer Research Grant, on behalf of a team that consists of a cancer biologist and biophysicist. This award will greatly enhance the existing collaboration of this exciting team that is focused on the condensate formed by mutant NPM1 in acute myeloid leukemia.

2021 Grantees

Research
KRAS is mutated in 95% of pancreatic ductal adenocarcinoma (PDA) and induces metabolic reprogramming and generation of reactive oxygen species (ROS). While ROS are highly labile, the Chio lab recently found that one of their oxidation products is stable on proteins and specifically enriched in PDA cells. Using mouse models and patient sera, the Chio lab proposes to apply chemical proteomic tools to identify oxidation products that will discriminate between PDA and benign disease such as pancreatitis. These experiments will setup a discovery pipeline for the exploration of new diagnostics and contribute to the development of early detection and therapeutic strategies in the clinic.

Biography
Dr. Christine Chio earned her PhD at the University of Toronto studying the interplay between innate immunity and cancer development. Subsequently, she joined Cold Spring Harbor Laboratory to pursue her postdoctoral training. Since then, her research has focused on understanding the role of cellular redox regulation, particularly in the development of pancreatic cancer. She is currently an Assistant Professor of Genetics and Development in the Institute for Cancer Genetics at Columbia University Medical Center.

Acknowledgement of Support
The AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant will catapult our efforts to address an important knowledge gap in cancer redox biology and to develop effective, redox-based early detection strategies for pancreatic cancer and other malignancies.

Research

Recurrent hotspot somatic mutations in genes encoding splicing factors (SFs) are very commonly found in myelodysplastic syndrome (MDS) and in other cancers at varying frequencies, but remain undruggable and the mechanisms by which they drive malignancy remain elusive. Dr. Papapetrou’s lab recently discovered a novel convergent effector of SF mutations, a long isoform of GNAS (the gene encoding the alpha subunit of the stimulatory G protein, G⍺s), as a novel target for MDS and other SF-mutant cancers. They aim to investigate G⍺s as a therapeutic target and evaluate therapeutic interventions that inhibit signaling downstream of its long form (G⍺s-L) using iPSC-derived and primary MDS cells in in vitro and in vivo functional assays.

Biography

Eirini Papapetrou, MD, PhD, is an Associate Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. Her research program seeks to uncover new disease mechanisms and therapeutic targets for myeloid neoplasms. Her laboratory pioneered the development of iPSC models of myeloid malignancies. Dr. Papapetrou is the recipient of several awards, including the American Society of Gene and Cell Therapy Outstanding New investigator Award, Damon Runyon-Rachleff Innovation Award, Pershing Square Sohn Prize and is an elected member of the American Society for Clinical Investigation.

Acknowledgement of Support

I am honored and grateful to receive this award, which will enable my laboratory to embark on a new and exciting direction in cancer biology of evaluating a new therapeutic target for cancers with splicing factor mutations.

2020 Grantees

Research
Dr. Buhrlage is set to develop a novel class of agents, bivalent deubiquitinase (DUB) proximity inducing molecules, that can selectively stabilize targeted proteins. This new drug development paradigm is enabled by her group’s recent success in developing selective DUB ligands for several members of the enzyme family.

Biography
Dr. Buhrlage completed a PhD in organic chemistry in 2008 at the University of Michigan and trained for two years in medicinal chemistry at the Broad Institute. Prior to joining as a faculty member in 2015, Dr. Buhrlage ran the medicinal chemistry core laboratory at Dana-Farber. She is currently an assistant professor in Dana-Farber’s Cancer Biology Department and Harvard Medical School’s Biological Chemistry and Molecular Pharmacology Department. Her research group focuses on the development of small molecule modulators of deubiquitylating enzymes (DUBs) for cancer therapy.

Acknowledgment of Support
I’d like to sincerely thank the AACR and MPM for the opportunity to pursue this “high-risk, high-reward” research project. As an early career investigator, the chance to pursue this type of project could propel my career. We will pursue the research aggressively and are optimistic we’ll credential a new cancer treatment paradigm.   

Research
Resistance to cancer immunotherapy is common, owing to tumor induced T cell dysfunction. Dr. Eil’s work demonstrated for the first time that potassium (K+) is elevated within cancers and deters T cell antitumor functions (Eil et al, Nature 2016; Science 2019). In this project, he will test the hypothesis that cancer cell death suppresses T cell function through K+ sensitive signal transduction. He is set to 1) determine the functional significance of cancer cell death byproducts for inflammasome and T cell activation in human Intrahepatic Cholangiocarcinoma (ICC), 2) define the mechanism underlying K+ control of T cell function, and 3) assess the impact of interventions to reprogram T cell K+ transport as cancer immunotherapeutics.

Biography
Dr. Eil completed a research fellowship at the Surgery Branch of the National Cancer Institute during his surgical training, focusing on T cell biology and tumor immunology. Following his clinical fellowship in surgical oncology (MSKCC), he returned to Oregon Health & Science University with appointments in the Departments of Surgery and Cellular, Developmental and Cancer Biology. Dr. Eil is a surgeon-scientist focused on applying immunotherapy to cancers involving the liver, pancreas, and bile ducts. His multidisciplinary expertise provides a unique perspective on alleviating suppression of T cell function in cancer to improve the lives and outcomes of patients.

Acknowledgment of Support
Receipt of this 2020 AACR-MPM Oncology Transformative Cancer Research Grant represents a critical milestone in my development as an independent scientist. I am thrilled to have the opportunity to pursue this exciting line of investigation with the potential to apply ground-breaking immune-based treatments to patients with treatment-resistant cancers.

Research
Given the current understanding of cancer progression as an evolutionary process, there is a largely unexplored possibility that cancer cells may engineer their own regulatory pathways. The discovery and characterization of such cancer-emergent regulatory mechanisms forms the foundation of the research proposed by Dr. Goodarzi and his team. Their recent discovery of orphan non-coding RNAs (oncRNAs) as a cancer-specific class of small RNAs with regulatory potential provides an opportunity for a systematic search for functional neo-regulators of gene expression in cancer cells. In addition to providing much needed insight into tumor evolution, this research also nominates novel targets that are solely active in cancer cells and whose targeted inhibition is unlikely to elicit on-target systematic toxicity.

Biography
With a dual background in computational and experimental cancer biology, Dr. Goodarzi brings a multidisciplinary approach to studying tumor progression. He is currently an assistant professor at the University of California, San Francisco. His research is focused on developing strategies that enable an unbiased search for previously unknown pathways of metastasis. By developing novel technologies for genome-wide measurement of hard-to-quantify RNA molecules, he has made key discoveries about the role of oncRNA, tRNAs, and tRNA fragments in cancer metastasis. On the computational front, he is focused on building network analytical models that help elucidate key pathways and processes that drive human disease.

Acknowledgment of Support
The AACR-MPM Transformative Cancer Research Grant provides a unique opportunity for my team to tackle a high-risk, high-reward project. In addition to providing support and resources, this represents a vote of confidence in our approach from the leaders in the field.

2019 Grantees

Research
Induction of ferroptosis (FO), a cell death pathway mediated by oxidative stress, may be a successful therapeutic approach for the treatment of multiple forms of cancer. Although high levels of lipid peroxides can trigger FO, little is known about how lipid peroxides signal and induce FO. Dr. Bar-Peled aims to develop and employ highly innovate proteomic and metabolomic technologies to test the hypothesis that lipid peroxide modification of proteins is a mechanism for signal transduction and FO induction.

Biography
Dr. Bar-Peled received his PhD in biology from the Massachusetts Institute of Technology. As a Damon Runyon postdoctoral fellow at the Scripps Research Institute, he focused on the response of cancer cells to oxidative stress. He is currently an assistant professor at the Center for Cancer Research at the Massachusetts General Hospital and the Department of Medicine at Harvard Medical School.

Acknowledgment of Support
It is a tremendous honor to be awarded this prestigious grant. We are now emboldened to undertake creative and cutting-edge research to address fundamental biochemical mechanisms by which cancer cells adapt to metabolic stress. The goal is to translate these basic discoveries into therapeutic insights for cancer patients.

Research
In a subtype of blood cancers called myeloproliferative neoplasms (MPN), the same mutation can result in drastically different disease phenotypes in different patients. This disconnect between genotype and phenotype is partly because the same mutation can have different consequences depending on the identity of the hematopoietic cell in which the mutation first occurs and the extent to which the population of mutated cells expands. Dr. Hormoz aims to 1) identify the disease-initiating cancer stem cell and characterize its differentiation dynamics in patients by sequencing the full transcriptome and the cancer mutations of individual cells and 2) reconstruct the genealogy of the cancer cells (and infer the history of disease progression) in patients from the pattern of accrued somatic mutations in individual cancer cells.

Biography
Dr. Hormoz obtained his PhD in applied physics at Harvard University. His postdoctoral studies were conducted jointly as a theorist at the Kavli Institute of Theoretical Physics (UCSB) and as an experimental systems and synthetic biologist at Caltech. Currently, he is an assistant professor with the Department of Data Sciences at the Dana-Farber Cancer Institute and the Department of Systems Biology at Harvard Medical School.

Acknowledgement of Support
I am thrilled to be a recipient of this AACR-MPM grant and to work closely with the AACR. This award recognizes the importance of innovative research and gives my lab the freedom to tackle fundamental questions in blood cancers using creative and risky approaches that otherwise would not be possible.