# CARP-1: A Potential Therapeutic Agent for Breast Cancer

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2021 · —

## Abstract

Development of new and improved strategies for triple-negative breast cancer (TNBC) treatment is urgently
needed since molecular complexity of TNBC together with therapy-associated side effects and emergence of
drug-resistance often limit effectiveness of current therapies. CARP-1/CCAR1 is a ubiquitous, phospho-protein
that can induce proliferation and apoptosis through multiple mechanisms. CARP-1 transduces chemotherapy
(adriamycin, etoposide, or Iressa)-dependent inhibitory signaling, and co-activates Adriamycin (ADR)-induced
p53. CARP-1 also co-activates cell-cycle regulatory anaphase-promoting complex (APC/C) E3 ubiquitin ligase
and steroid/thyroid receptors. Here we report that CARP-1 interacts with ERKs, and binds with NEMO (NF-B
Essential Modulator; NF-B-activating kinase IKK subunit ). Our preliminary and published studies revealed
that ADR induced CARP-1 threonine627 phosphorylation, ERK activation, and canonical NF-B pathway that
involved NEMO-CARP-1 binding. Importantly, inhibition of NEMO-CARP-1 binding diminishes NF-B activation
(noted by phosphorylation of p65/RelA) by ADR but not by TNFα, interleukin (IL)2, or EGF. Further, SNI-1, a
novel SMI of NEMO-CARP-1 binding, enhances ADR or Cisplatin inhibition of TNBC cells, diminishes levels of
genotoxic stress (ADR or Cisplatin)-induced pro-inflammatory cytokines TNFα and IL8. SNI-1 enhances TNBC
growth suppression by ADR or Cisplatin in vivo in 4T1 syngeneic tumor model.
Hypothesis: DNA Damage-inducing drugs (ADR, Cisplatin) activate CARP-1-mediated canonical NF-B and
ERK pathways. The rationale for this hypothesis include our preliminary and published studies that indicate
inhibition of therapy-induced, canonical NF-B activation by disruption of NEMO-CARP-1 binding enhances
efficacy of ADR and Cisplatin in vitro and in vivo. Moreover, ADR also induces CARP-1 phosphorylation and,
since genotoxic therapy also activates ERKs, targeting of NEMO-CARP-1 binding together with ERK inhibitors
will result in greater tumor suppression by ADR or Cisplatin. Thus, targeting of CARP-1/NEMO binding could
permit us to overcome chemo-resistance in TNBCs without affecting other central functions of NF-B induced
by TNFα, IL2, and/or EGF signaling necessary for host tissue homeostasis. We will conduct following three
aims to test our hypothesis.
Aim 1: To define role of CARP-1 in genotoxic chemotherapy-induced canonical NF-B survival pathway. SNI-1
inhibits therapy-induced NEMO phosphorylation. We will elucidate how SNI-1 inhibits DNA damage-induced,
NEMO phosphorylation and canonical NF-B pathway.
Aim 2: To investigate mechanism(s) by which CARP-1 interacts with ERKs. We will determine how targeting of
ERKs in combination with SNI-1 enhances efficacy of genotoxic chemotherapy.
Aim 3: To demonstrate targeting of CARP-1/NEMO-dependent canonical, NF-B signaling by water-soluble
SNI-1 alone or coupled with targeting of ERKs by therapeutics currently in clinical trials/use, will result in
superior T...

## Key facts

- **NIH application ID:** 10125709
- **Project number:** 1I01BX004931-01A2
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Arun Kumar Rishi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125709

## Citation

> US National Institutes of Health, RePORTER application 10125709, CARP-1: A Potential Therapeutic Agent for Breast Cancer (1I01BX004931-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10125709. Licensed CC0.

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