# Studies on the effects of a novel intermittent therapy on intratumoral clonal architecture and resistance

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $410,835

## Abstract

ABSTRACT
While it is well established that tumors evolve as they adapt to environmental cues, exactly how this process
occurs remains under investigation. Precision medicines impose a relatively uniform selective pressure on the
tumor and have well-described mechanisms of action, which enable a unique opportunity to study the
determinants of evolutionary selection. By utilizing such treatments in conjunction with newly established
methodologies that enable single-cell sequencing and prospective tracking of subclonal populations, this
proposal aims to provide insight into the principles that govern the selection of resistance-causing alterations.
BRAF mutant tumors were selected as an experimental model system because these are found in
approximately 7% of cancer patients, including those with malignant melanoma, thyroid, colorectal and lung
cancers. While RAF and/or MEK inhibitors are clinically effective active against these tumors, resistance is
inevitable and almost all patients die from their disease, indicating the need to identify improved therapies. In
recent work, we have established a conceptual framework that explains the selection and propagation of
resistance-causing alterations and identified an intermittent three-drug combination therapy, which has a
potent antitumor effect in BRAF V600E mutant lung cancer and melanoma patient-derived xenograft models.
Based on these advances, we now proposed to study the effect of this treatment on intratumoral clonal
heterogeneity and the emergence of resistance. In aim 1 we will determine genetic alterations that confer
resistance to the intermittent combination treatment and determine the effect of this therapy on the intratumoral
heterogeneity. In aim 2 we will prospectively evaluate the effect of therapy on clonal selection. In aim 3 we will
investigate the mechanisms that confer fitness to the subclones that are selected during therapy. The impact of
this proposal centers on advancing our understanding of the dynamics that drive the selection of
subpopulations harboring resistance-causing alterations and on the identification of novel and more effective
treatments for patients with BRAF mutant tumors.

## Key facts

- **NIH application ID:** 9872136
- **Project number:** 5R01CA230267-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Piro Lito
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,835
- **Award type:** 5
- **Project period:** 2019-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872136

## Citation

> US National Institutes of Health, RePORTER application 9872136, Studies on the effects of a novel intermittent therapy on intratumoral clonal architecture and resistance (5R01CA230267-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872136. Licensed CC0.

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