# ROLE OF MIDKINE IN MOLECULAR TARGETED THERAPY TO TIP1 FOR LUNG CANCER TREATMENT

> **NIH NIH K22** · WASHINGTON UNIVERSITY · 2020 · $153,211

## Abstract

PROJECT DESCRIPTION/ ABSTRACT
Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities world-wide. Molecular
targeted therapy is a growing topic of investigation to improve therapeutic efficacy for NSCLC. A few targeted
therapies that exploit aberrant protein expression profiles have been approved for NSCLC. However, the
marginal percentage of cancers with improved efficacy observed with these therapeutic approaches highlights
the need for discovery of additional molecular targets. The proposed research is significant as it will generate
new molecular targets and treatment strategies for NSCLC therapy. We propose targeting of the scaffold
protein TIP1 that is a novel target for lung cancer as identified by analysis of the cancer genome atlas datasets
and NSCLC tumor tissue microarrays. The functional domain of TIP1 (PDZ domain) caps the C-terminus of
many different cellular proteins that regulate important cellular functions. Knocking down TIP1 revealed that it
plays an important role in cell signaling, cancer development, and progression making it an attractive target for
anticancer therapeutics. Comparing antibodies targeting different epitopes of TIP1, it was found that antibodies
against the PDZ domain of TIP1 were most effective in inducing direct cytotoxicity of lung cancer cells but not
normal cells. Anti-PDZ/TIP1 antibodies injected into mice bearing lung cancer bind specifically to cancer cells
and substantially enhance tumor control. Quantitative mass spectrometry identified Midkine (MDK) as a
putative protein that modulates this cytotoxicity by anti-PDZ/TIP1 antibodies. Additional studies suggested that
the β-catenin/Wnt signaling may be involved in this up-regulation of MDK after blocking of TIP1. Together,
these studies led to the central hypothesis that MDK is upregulated by the anti-PDZ/TIP1 antibody via the β-
catenin/Wnt signaling pathway, which subsequently modulates downstream cell death mechanisms. Aim 1 will
elucidate the mechanisms of induction of MDK following blockade of the PDZ domain of TIP1. This aim will
lead to identification of novel molecular targets for NSCLC treatment that have never been considered before.
Aim 2 will evaluate the efficacy of blocking TIP1 function while simultaneously blocking MDK function in mouse
models of NSCLC. This aim will guide the development of combination therapies to optimize efficacy of
NSCLC treatment. This research is innovative because we are studying a novel molecular target, TIP1.
Blocking the functional domain of TIP1 leads to NSCLC cell death. We also propose an innovative strategy of
dual targeting TIP1 and MDK to enhance the therapeutic efficacy of NSCLC. Building on my cancer biology
background, this K22 award will allow me to train in cutting edge proteomic and genomic approaches with
special emphasis on identifying novel NSCLC molecular targets. I have proposed a research and training plan
that will equip me with the highest skills to ensure my...

## Key facts

- **NIH application ID:** 9821674
- **Project number:** 1K22CA234404-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Vaishali Kapoor
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $153,211
- **Award type:** 1
- **Project period:** 2020-07-07 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9821674

## Citation

> US National Institutes of Health, RePORTER application 9821674, ROLE OF MIDKINE IN MOLECULAR TARGETED THERAPY TO TIP1 FOR LUNG CANCER TREATMENT (1K22CA234404-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9821674. Licensed CC0.

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