# Interrogating the Evolutionary Dynamics of Cancer for Clinical Benefit and Actionability

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $944,561

## Abstract

Project Abstract
PDA is the most common neoplasm of the pancreas, and is soon to be the second most common cause of
cancer deaths in the United States. Surgical resection in Stage I/II patients provides the only opportunity for
cure, yet >80% of patients will recur and die of their disease within 2-3 years2. The statistics for Stage III and
Stage IV PDA are more dismal, having 12 and 6 month median overall survival times, respectively. Outside of
BRCA2 mutations that confer sensitivity to platinum salts or PARP inhibition, or immune checkpoint inhibitors
in patients with mismatch repair deficiency, there are few actionable targets in the PDA genome. Thus, it is
essential that novel strategies are developed to extend survival. One innovative way to do so is to “treat
evolution with evolution”. However, it is first imperative that we develop a deep understanding of PDA
evolutionary biology. Our efforts will be focused on three questions with clear mechanistic and translational
relevance to this ultimate goal. First, what are the features of clinically relevant intratumoral heterogeneity at
the genetic and transcriptional level? Second, how do cell autonomous and non-cell autonomous factors
influence the evolutionary dynamics of PDA? Third, how do PDA therapies influence evolutionary trajectories,
and can they be more effectively used within the evolutionary context of a tumor? We will rely on whole exome
or whole genome sequenced samples of primary and metastatic pancreatic cancer tissues, single cell
technologies for copy number alterations or RNA expression, long-term evolution experiments, mouse models
and computational models to address these questions. We aim to use the information gained over the period of
this work to develop metrics of heterogeneity that will inform clinical management, including identification of the
optimal agents and timing of administration based on the evolutionary context of the patients' PDA. Such
questions are of broad interest in cancer biology in general and have a strong likelihood to impact upon other
tumor types as well.

## Key facts

- **NIH application ID:** 9981685
- **Project number:** 5R35CA220508-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Christine A Iacobuzio-Donahue
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $944,561
- **Award type:** 5
- **Project period:** 2018-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981685

## Citation

> US National Institutes of Health, RePORTER application 9981685, Interrogating the Evolutionary Dynamics of Cancer for Clinical Benefit and Actionability (5R35CA220508-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9981685. Licensed CC0.

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