# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · JOHN D DINGELL VA MEDICAL CENTER · 2024 · —

## Abstract

Inflammation is the body's attempt at self-protection to remove harmful stimuli and begin the healing process.
Chronic inflammation can eventually cause several diseases and conditions, including cancers, rheumatoid
arthritis, atherosclerosis, and plays a role in heart disease. The overarching goals of nominee’s research involve
elucidating molecular underpinnings of cell growth/survival and death/apoptosis with particular reference to
cancer, atheroscleroscosis, and cardiovascular hypertension.
 The American Cancer Society estimates highest percent of new cases and mortality resulting from lung
and breast cancers in females, while prostate and lung cancers account for highest percentage of new cases
and associated mortality among men. Overall incidence rates and mortality due to lung and breast cancers have
decreased over last decade partly due to advances in diagnosis and therapeutics, particularly targeted
therapeutics for a number of cancers including the non-small cell lung cancers (NSCLCs). However, adaptive
genetic alterations and mutations in cancers contribute to therapy failures and relapses in clinic occur that often
result in emergence of resistant, hard to treat disease, and warrant development of new therapeutic strategies
to overcome drug resistance and improve therapeutic outcomes.
 By utilizing a functional gene-knockout approach the nominee identified a novel, apoptosis inducing
protein termed CARP-1/CCAR1 (J. Biol. Chem. 278: 33422-33435, 2003). CARP-1 regulates apoptosis
signaling induced by diverse therapeutics such as Adriamycin, Etoposide, and Gefitinib (Oncotarget 6(9): 6499-
510, 2015). Following CARP-1 discovery, the nominee conducted a chemical-biological approach to identify
novel small molecule CARP-1 Functional Mimetic (CFMs) compounds (J. Biol. Chem. 286 (44): 38000-38017,
2011). CFMs inhibit growth of therapy-resistant triple-negative breast cancers (TNBC) and non-small cell lung
cancers (NSCLCs) in part by inducing CARP-1-dependent apoptosis (Oncotarget, 7(45): 73370–73388, 2016;
8(62):104928-104945, 2017; 9(51): 29680-29697, 2018). During RCS funding, nominee made a fundamental
observation that CARP-1 interacts with NF-κB kinase subunit gamma (IKKγ). This interaction functions to
activate NF-κB-dependent cell survival and growth in genotoxic chemotherapy-treated cancer cells (J. Biol.
Chem. 295: 3532-3552, 2020). Targeting of IKKγ-CARP-1 binding prevents therapy-induced NF-κB activation.
On the basis of this finding nominee discovered new compounds, termed selective NF-κB inhibitors (SNIs), that
target IKKγ-CARP-1 binding to attenuate therapy-induced survival pathways and enhance efficacy of cisplatin in
preclinical tumor models of breast and renal cancers. Given that cisplatin is widely used anti-cancer therapeutic
in BRCA-mutant breast, non-small cell lung, and kidney cancers, SNI compounds will provide a novel avenue to
improve chemotherapy efficacy and attenuate emergence of drug-resistant cancers. The nomine...

## Key facts

- **NIH application ID:** 10720899
- **Project number:** 5IK6BX004015-07
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Arun Kumar Rishi
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10720899

## Citation

> US National Institutes of Health, RePORTER application 10720899, BLRD Research Career Scientist Award Application (5IK6BX004015-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10720899. Licensed CC0.

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