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.
AACR NextGen Grant for Transformative Cancer Research
Paul A. Northcott, PhD
St. Jude Children's Research Hospital
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
Fred Hutchinson Cancer Research Center
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
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
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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