# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · JESSE BROWN VA MEDICAL CENTER · 2022 · —

## Abstract

Project Summary/Abstract:
The main focus of research in our group is to understand the underlying molecular mechanisms of pancreatic
and breast cancer pathogenesis. The overarching goal of our research is to investigate how the cellular pathways
(i.e. circuits) are dysregulated and can lead to uncontrolled cell growth (i.e. cancer). The ultimate goal is to
develop and use small molecules to target the dysregulated proteins that are the underlying cause of pancreatic
and breast cancers pathogenesis.
Our laboratory has been working with a group of proteins, called Mixed Lineage Kinases (MLKs). The roles of
MLKs in cancer is an emerging area and the inhibitor of this family has gone through clinical trial for Parkinson's
Disease. We have shown that inhibitor of MLKs can be repurposed to treat Triple Negative breast cancer (TNBC)
and pancreatic ductal adenocarcinoma (PDAC).
Our recent results (funded through VA-Merit) demonstrate that one of the MLK family member, MLK3 was highly
overexpressed in human pancreatic cancer tumors and was necessary for cell growth. Furthermore, using animal
models of pancreatic cancer, we have observed that MLKs inhibitor ameliorate PDAC and the animals survive
much longer, compared to vehicle treated animals. We plan to further explore how MLK3 dysregulation promotes
pancreatic cancer and ultimately use the inhibitors for therapeutic intervention.
The other two projects (funded through 2 NCI/NIH grants) are on breast cancer. We reported earlier that
suppression of MLK3 activity by Estrogen was necessary for ER+ breast cancer cell survival and growth. We
also observed that the other receptor, HER2 was also able to suppress MLK3 activity in HER2+ breast cancer
and this was also necessary for their survival. Taken together, these exciting results suggest that suppression
of MLK3 by ER and HER2 provides survival signals for breast cancer cell growth and proliferation. Therefore,
we developed a novel nanoparticle, loaded with MLK3 activator, ceramide (a lipid) that was able to induce
significant cell death in HER2+ and ER+ breast cancer cells. In animal models of ER+ and HER2+ breast cancer,
the ceramide-nanoparticle was able to reduce tumor burden. In addition, we also observed that in human TNBC
tumors, the activity of MLK3 was very high compared to ER+ breast cancer tumors. Through mechanistic studies,
we identified that MLK3 activity plays paradoxically a survival role in TNBC. Based on our cellular and human
tumor data, the animal transplanted with TNBC tumors (i.e. PDXs) were treated with MLKs inhibitors, indeed the
tumor burden was reduced and the animal life was prolonged. Our results are first in line to demonstrate that
MLK3/MLKs inhibitors can significantly reduce TNBC tumor burden and can prolog animals' life. Similarly,
following our cellular and human tumor data, the tumor burden of Herceptin (i.e. anti-HER2+ therapy) resistant
human tumors in animal (i.e. PDXs) was reduced.
Taken together, our results suggest ...

## Key facts

- **NIH application ID:** 10293579
- **Project number:** 5IK6BX004855-03
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** AJAY NMN RANA
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293579

## Citation

> US National Institutes of Health, RePORTER application 10293579, BLR&D Research Career Scientist Award Application (5IK6BX004855-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293579. Licensed CC0.

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