# A two-pronged “senolytic” approach to treatment of oral cavity cancer

> **NIH NIH R03** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $168,000

## Abstract

ABSTRACT
Standard therapies (surgery, radiation, and cisplatin) for oral cavity squamous cell carcinoma
(OCSCC) have not changed for decades, and no molecularly targeted agents have an
established role as first-line treatment. Unlike HPV-positive oropharynx cancer, which has an
excellent prognosis, advanced OCSCC (which is predominantly HPV-negative) carries a high
recurrence rate (~20-30%) and poor overall survival (~50% at 5 years).
 The biology of OCSCC is well described. Loss of p16INK4A (p16) function is the driving
defect in cell cycle regulation. p16 inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), which
leads to cell cycle arrest in G1. The FDA-approved cancer therapeutic, palbociclib, is a small
molecule inhibitor that targets CDK4/6. Our preliminary work shows that palbociclib consistently
induces senescence in OCSCC cells. We have also shown that these cells consistently
upregulate the pro-survival molecule, BCL-xL, in response to palbociclib.
 There has been growing interest in targeting senescent cells in cancer. Though senescent
cells do not proliferate, they have been shown to produce inflammatory signals that promote
and support neighboring cancer cells in the tumor micorenvironment. There has been growing
interest in agents that specifically target senescent cells (‘senolytics’). Perhaps the most well-
studied senolytic, ABT-263 (navitoclax), targets BCL2 family pro-survival anti-apoptotic signaling
molecules, BCL2, BCL-xL, and BCL-w. Our preliminary work has shown that combining
palbociclib (inducing senescence) with navitoclax (senolytic) results in profound apoptosis in
OCSCC cells.
 In this proposal, we aim to study the palbociclib/navitoclax combination extensively in
OCSCC. In Specific Aim #1, we will study the response to palbociclib in a panel of OCSCC cell
lines, and concurrently in a ‘cell reprogramming’ model, which allows perpetual culture of
primary OCSCC tumor cells derived from patients treated at our own institution. We will
specifically measure the senescence response (Specific Aim#1a) and apoptosis signaling using
a high throughput method called ‘BH3’ profiling (Specific Aim1b). In Specific Aim#2 we will
measure synergy between palbociclib and ABT-263 (navitoclax) using cell viability assays, and
evaluate in vivo efficacy using an orthotopic tongue xenograft model of OCSCC.

## Key facts

- **NIH application ID:** 10287086
- **Project number:** 1R03DE031001-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Thomas Julian Ow
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $168,000
- **Award type:** 1
- **Project period:** 2021-07-02 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287086

## Citation

> US National Institutes of Health, RePORTER application 10287086, A two-pronged “senolytic” approach to treatment of oral cavity cancer (1R03DE031001-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10287086. Licensed CC0.

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