# Targeting polo-like kinase for therapy of small cell lung cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $630,466

## Abstract

PROJECT SUMMARY/ABSTRACT
Small cell lung cancer (SCLC) is a significant health problem projected to afflict more than 35,000 new patients
in the US in 2021. Less than 20% of newly diagnosed patients survive beyond 2 years. New and effective
treatments are urgently needed to improve the poor outcome associated with this disease. SCLC is one of the
most genomically unstable tumors but genomic-informed targeted therapy is currently not an established
strategy in this disease. This is in part because most of the alterations in SCLC involve tumor suppressor
genes such as TP53 and RB1, which cannot be targeted directly. We contend that while tumor suppressor
gene alterations are not ideal targets for drug development efforts, the biological vulnerability conferred by
these alterations can be exploited for therapeutic gains in SCLC. We employed an unbiased and agnostic
preclinical screening to test several classes of targeted agents in a panel of SCLC cell lines. We discovered
exquisite in vitro activity of four different polo like kinase 1 (PLK1) enzyme inhibitors, rigosertib, volasertib,
CYC140 and Onvansertib. We subsequently confirmed the in vivo efficacy using traditional xenograft and
patient-derived xenograft models of SCLC. We made the intriguing observation that SCLC cell lines harboring
inactivating TP53 gene mutations are more sensitive to PLK1 inhibitors. We replicated this interesting
observation using genetic depletion of wild type TP53 and overexpression of active mutant form of p53. These
data therefore suggest that specific types of TP53 mutation could serve as potential predictive biomarkers to
guide the development of PLK1 inhibitor as therapy of SCLC. We propose to test the hypotheses that (i.)
Onvansertib, a potent PLK1 inhibitor, will have significant anticancer efficacy in relapsed SCLC patients and
(ii.) Disruptive, inactivating TP53 gene mutation will predict efficacy of PLK1 inhibitors in patients. Also, that
YAP1 positive subtype of SCLC will be vulnerable to PLK1 inhibitors alone and the combination with immune
checkpoint blockade will further enhance efficacy in this subset of SCLC. We will pursue three innovative,
independent but integrated specific aims: Aim 1: Conduct a phase II co-clinical trial to systematically assess
the efficacy of onvansertib in patients with relapsed SCLC. A 2-stage phase II clinical trial will evaluate the
efficacy of onvansertib in relapsed SCLC patients. Aim 2: Interrogate putative predictive biomarkers and
elucidate whether and how inactivating TP53 gene mutations confer vulnerability to PLK1 inhibitors in SCLC.
Preclinical efficacy of PLK1 inhibitors will be assessed in a large panel of genomically characterized SCLC cell
lines. Activity will be correlated with specific types of TP53 mutations and with other biologically relevant
genetic alterations in SCLC. Aim 3: Characterize mechanism(s) of acquired resistance to PLK1 inhibitor in
SCLC and combination strategies to overcome resistance and e...

## Key facts

- **NIH application ID:** 10503509
- **Project number:** 1R01CA273216-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Taofeek K Owonikoko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $630,466
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10503509

## Citation

> US National Institutes of Health, RePORTER application 10503509, Targeting polo-like kinase for therapy of small cell lung cancer (1R01CA273216-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10503509. Licensed CC0.

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