# Translational Research Career Development: Overcoming Resistance to Radiotherapy

> **NIH VA IK2** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2020 · —

## Abstract

Head and neck cancer (HNC) is the sixth most common malignancy worldwide, diagnosed twice
as frequently in veterans. Radiation therapy (RT) is an important component of cancer
treatment; however, its efficacy is limited by radioresistance, with the cancer sometimes
returning within the treated area. Resistance to RT is, at least in part, mediated by adaptive
signaling events induced by treatment. However, we do not yet understand the pathways used
by cells to evade the cellular damage caused by RT. The long-term goal is to better understand,
and subsequently target, the mechanisms of resistance that cancer cells use to evade a
radiation-induced death. Combinatorial adaptive response therapy (CART) represents a novel
platform that allows for the rapid and systematic identification of treatment combinations that
overcome therapeutic resistance and result in synthetic lethality. CART takes advantage of
Reverse Phase Protein Microarray Analysis (RPPA), providing a high throughput, sensitive, and
quantitative approach to analyze differential protein expression to identify targets for
combinatorial therapy. The applicability of the CART approach to RT has not previously been
investigated. The central objective of this career development application is to develop myself
as an independent translational scientist with expertise in HNC, and to become a leader in the
field of translational oncology, with implementation of a CART approach to increase the efficacy
of RT in 3D culture and xenograft models. The rationale for the proposed research is rationally
combining newly identified systemic treatments, such as the glutaminase inhibitor, CB-839, with
RT will result in maximal efficacy while minimizing potential toxicities. Guided by strong
preliminary data implicating glutaminase as playing a role in adaptive resistance to RT, we will
pursue three specific aims: First (SA1), we will determine whether the combination of RT with a
glutaminase inhibitor (CB-839) results in decreased aerobic respiration and increased cell death
in 2D and 3D culture. To pursue this, upregulated aerobic respiration pathways, including those
catalyzed by glutaminase, will be selectively targeted alone or in combination with RT in 3D with
analysis of proliferation and apoptosis markers. Seahorse technology will be used to assess
aerobic respiration. Second (SA2), we will validate the efficacy of glutaminase inhibition by
testing it both alone and in combination with RT in preclinical heterotopic cell line and patient-
derived xenograft animal models. Finally (SA3), we will identify other novel HNC signaling
pathways that are significantly altered by RT using RPPA. For this aim, spheroids grown from
oral cavity tumor derived cell lines will be grown in 3D culture and subjected to non-lethal RT
doses with protein levels assessed by RPPA to identify candidate target proteins that are
differentially expressed with RT. This innovative approach uses a cutting-edge, high-throughput,
sensi...

## Key facts

- **NIH application ID:** 9892870
- **Project number:** 5IK2BX004360-02
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** Vinita Takiar
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892870

## Citation

> US National Institutes of Health, RePORTER application 9892870, Translational Research Career Development: Overcoming Resistance to Radiotherapy (5IK2BX004360-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892870. Licensed CC0.

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