# Intratumor heterogeneity and therapeutic resistance

> **NIH NIH R00** · SCRIPPS FLORIDA · 2020 · $248,999

## Abstract

PROJECT SUMMARY/ABSTRACT
Cellular diversity within a tumor is one of the main causes of cancer treatment failure. Presence of distinct
subpopulations of cells with different sensitivity to any given therapy increases the chance of resistance
and tumor recurrence. Therefore, understanding of mechanism governing the intratumor heterogeneity is
vital for designing more effective regimens. Within the mentored phase of the proposal I am planning to
investigate the influence of intratumor heterogeneity on HER2-targeted therapies in HER2+ breast cancer
(Aim 1). In my preliminary study I used STAR-FISH, a novel method I developed allowing for simultaneous
detection of point mutation and gene amplification at single cell level in intact tissue slides, to assess
genetic heterogeneity and spatial distribution of subpopulations of cells in matched therapy naïve and post-
chemotherapy samples. We have found that changes in cellular diversity upon chemotherapy can predict
patient outcome. Thus, in the current proposal I will test the hypothesis that emerged from those studies:
intratumor heterogeneity could have a pronounced effect on targeted treatment. I will investigate this effect
on samples of HER2+ breast cancers undergoing novel anti-HER2 regimen (Aim 1.A). I will also dissect the
role of a point mutation in PIK3CA in epigenetic and phenotypic plasticity of HER2+ breast cancer cells (Aim
1.B). To uncover the mechanism that sustains intratumor heterogeneity in those tumors I will characterize
the interactions between genetically distinct subpopulations (Aim 2). To accomplish the goals described in
this proposal, I will use novel and unique techniques, validated in my previous studies.
In the independent phase of the award I will concentrate my research efforts on highly aggressive brain
tumors. These tumors display profound degree of intratumor heterogeneity and the current therapeutic
interventions fail to significantly prolong lives of patients with this disease. Therefore, I am strongly
motivated to study the genetic intratumor heterogeneity in gliomas (Aim 3). I will focus on the
characterization of genetic diversity in the process of progression of low-grade glioma to glioblastoma and I
will analyze targeted treatment-induced changes in intratumor heterogeneity and their influence on patient
outcomes (Aim 3.A). I will also use a novel method to perform epigenetic profiling of genetically distinct
subpopulations of glioblastoma cells to investigate the interplay between genetic and epigenetic
heterogeneity (Aim 3.B). In summary, the proposed research will shed new light on therapeutic implications
of intratumor heterogeneity and will help designing more effective cancer treatment.
Throughout my scientific career I have demonstrated high productivity, devotion and strong technical skills,
which are crucial for the successful execution of the proposed research. I have a long-term interest in the
study of intratumor heterogeneity, as I have chosen the t...

## Key facts

- **NIH application ID:** 10000854
- **Project number:** 5R00CA201606-05
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Michalina Janiszewska
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000854

## Citation

> US National Institutes of Health, RePORTER application 10000854, Intratumor heterogeneity and therapeutic resistance (5R00CA201606-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10000854. Licensed CC0.

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