# A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2020 · $54,000

## Abstract

PROJECT SUMMARY
This is a Supplement for Dr. Kara Maxwell's Mentored Clinical Scientist Development Award (K08-CA215312).
K08-CA215312 was funded on 3/01/2018 and details a five year plan to promote the independent career of Dr.
Kara Maxwell as a physician scientist in translational cancer genetics. Dr. Maxwell is a PhD trained molecular
and cellular biologist who is board certified in Medical Oncology. Her clinical focus is in cancer risk evaluation.
Dr. Maxwell is currently an Assistant Professor of Medicine at the University of Pennsylvania and is mentored
for this K08 award in human genetics and genomics by Dr. Katherine Nathanson. Dr. Maxwell is interested in
inherited susceptibility to cancer and, specifically, how inherited mutations in DNA repair genes can direct
targeted treatment of cancer. Most tumors in patients with germline mutations in the homologous
recombination DNA repair genes BRCA1/2, respond to platinum agents and PARP inhibitors due to synthetic
lethality. However, tumors with primary and acquired resistance to these agents exist. Dr. Maxwell's
preliminary studies showed that absence of BRCA locus-specific loss of heterozygosity (LOH) is observed in
approximately 25% of primary BRCA1/2 germline mutation-associated breast and ovarian tumors. Her data
suggest that BRCA1/2 locus-specific LOH could be a mechanism of primary platinum and PARP inhibitor
resistance. K08-CA215312 aims to expand these preliminary studies into two clinically important categories of
patients: 1) patients with inherited BRCA1/2 mutations with non-breast/ovarian tumors (Aim 1) and 2) breast
cancer patients with inherited mutations in the DNA repair genes ATM and CHEK2, the two most commonly
identified genes in BRCA1/2 negative breast cancer patients (Aim 2). Some tumors with primary resistance to
platinum and PARP inhibitors demonstrate locus-specific LOH; therefore, other mechanisms exist.
Hypomorphic, or partially functional, mutations may retain sufficient DNA repair activity to lead to primary
resistance. Dr. Maxwell will test the hypothesis that hypomorphic BRCA2 mutations may demonstrate primary
PARP inhibitor resistance using CRISPR-Cas9 modelling of mutations in breast cancer cell lines (Aim 3). She
is supplementing these studies with a career development program that takes advantage of the resources of
the Basser Center for BRCA Research and broadly at UPenn. Dr. Maxwell's long-term goal is to develop a
career as a physician scientist running an independently funded laboratory studying inherited susceptibility to
cancer. She has strong institutional support for this goal, and she was provided institutional startup funds and
laboratory space upon her promotion to Assistant Professor on 07/01/2018. Unfortunately, three significant life
events have led to difficulties at this critical period – the death of her aunt for whom she was medical and
financial power of attorney and now estate executor, and medical issues with her father and daughter. This...

## Key facts

- **NIH application ID:** 10128910
- **Project number:** 3K08CA215312-03S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** KARA N MAXWELL
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $54,000
- **Award type:** 3
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128910

## Citation

> US National Institutes of Health, RePORTER application 10128910, A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes (3K08CA215312-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10128910. Licensed CC0.

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