# Identifying and targeting evolutionary trajectories in cancer

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $335,090

## Abstract

Project Summary/Abstract
Tumor evolution represents the fundamental obstacle to providing durable cures for cancer patients.
This problem has become increasingly apparent with the recent and clinical use of targeted
therapeutics. While small molecule inhibitors of cancer-promoting oncogenes have led to
unprecedented tumor regression in some leukemias, melanomas and non-small cell lung cancers,
these tumors inevitably relapse as chemorefractory (to the initial therapeutic) malignancies within a
year or two of initial treatment. In some cases, therapies exist to target drug resistant disease. Yet,
diverse mechanisms or “evolutionary trajectories” can lead to distinct forms of resistance to front-line
therapies, and each of these mechanisms may require a distinct second generation therapy. This
represents the current reality of targeted therapeutics, in which we treat relapsed tumors with agents
that target the drug resistant state, creating an unwinnable resistance arms race. Thus, modern
therapies have generally failed to yield prolongued cancer remission or disease management. In fact,
only BCR-ABL inhibitors in Chronic Myelogenous Leukemia have consistently achieved long-term
cancer remissions. We recently discovered a phenomenon of “temporal collateral sensitivity” in
leukemia, whereby distinct intermediate stages in the evolution of resistance to targeted therapeutics
present vulnerabilities for exploitation using small molecules from orthogonal drug classes. The
existence of these evolutionary vulnerabilities provides us with a means of blocking potential routes to
resistance and eradicating residual disease following front-line therapy. We believe this phenomenon
is relevant to many other cancer types. Here, we propose to characterize the mechanism of temporal
collateral sensitivity in BCR-ABL+ leukemia and ALK-driven lung cancer. We also plan to examine
how temporal collateral sensitivity can be exploited in preclinical settings to target evolutionary
trajectories towards drug resistance. We believe that this work will not only identify strategies for
preempt drug resistance, but also reveal ways to combine these strategies to promote durable
therapeutic responses.

## Key facts

- **NIH application ID:** 10450872
- **Project number:** 5R01CA233477-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Michael Hemann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $335,090
- **Award type:** 5
- **Project period:** 2019-08-14 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450872

## Citation

> US National Institutes of Health, RePORTER application 10450872, Identifying and targeting evolutionary trajectories in cancer (5R01CA233477-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10450872. Licensed CC0.

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