# Full Project 1: Understanding and Targeting of Convergent Immunosuppressive Pathways and Molecular Signaling in HPV-Positive and HPV-Negative Penile Cancer

> **NIH NIH U54** · UNIVERSITY OF PUERTO RICO MED SCIENCES · 2020 · $15,178

## Abstract

FULL PROJECT 1 - UNDERSTANDING AND TARGETING OF CONVERGENT IMMUNOSUPPRESSIVE
PATHWAYS AND MOLECULAR SIGNALING IN HPV-POSITIVE AND HPV-NEGATIVE PENILE CANCER
PROJECT SUMMARY/ABSTRACT
Penile cancer (PeCa) is a highly morbid disease that exhibits a higher mortality among Puerto Ricans than
among the rest of the US population. The theme of the U54 grant, Infection-Driven Malignancies Program for
Advancing Careers and Translational Sciences (IMPACT), fits well with our project because infection with
human papillomavirus (HPV) has been identified as a risk factor for penile cancer. The etiology of penile
cancer is incompletely understood. Therefore, there is an urgent need to address knowledge gaps. We
recently developed the first genetically engineered mouse (GEM) models of penile squamous cell carcinoma
(PSCC), the predominant histologic type of PeCa, through co-deletion of tumor suppressor genes (Smad4,
Apc) in mouse penile epithelium. We have also generated the first set of patient-derived xenograft (PDX)
models for PeCa (N=6). In our pilot project, using this GEM model of PSCC, we found: (1) substantial
infiltration of immune cells in the penile tumors, especially myeloid-derived suppressor cells (MDSCs) that can
inhibit cytotoxic T cells and cause immune evasion, and (2) strong cyclooxygenase-2 (COX2) expression in
penile tumors and PI3K/mTOR signaling in MDSCs. Further using expression arrays we identified novel
insights into expression patterns associated with human HPV+ and HPV- PeCa.The objective of this proposal is
to develop therapeutic strategies for PeCa and validate molecular pathways associated with HPV+ and HPV-
PeCa subtypes. Our hypotheses are that (1) PeCa formation is promoted by chronic inflammation as a result of
HPV infection or downregulation of essential tumor suppressor genes SMAD4 and APC, (2) The key signaling
hubs driving PeCa progression, including COX2 and PD-L1 upregulation, are effective targets for
immunotherapeutic intervention,and (3) Estrogen and Notch signaling are upregulated in HPV+ PeCa and play
important roles in PeCa progression. The specific aims of this proposal are to: (Aim 1) Eradicate mouse penile
cancer by combining targeted therapy and immunotherapy, (Aim 2) Identify the immunologic profiles
associated with HPV infection in human penile cancer to optimize therapy, and (Aim 3) Validate and target
both Estrogen and Notch signaling in HPV+ penile cancer. The proposed studies will have a significant impact
on both the understanding of the molecular pathways that drive HPV+ and HPV- PeCa subtypes and the
identification of effective therapeutic strategies to treat these highly morbid tumors. Through this unique
collaboration our multidisciplinary research teams from The University of Texas MD Anderson Cancer Center
and the University of Puerto Rico are poised make novel contributions to understanding and curing this rare
fatal cancer.

## Key facts

- **NIH application ID:** 10247763
- **Project number:** 3U54CA096297-17S1
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MED SCIENCES
- **Principal Investigator:** MAGALY MARTINEZ-FERRER
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $15,178
- **Award type:** 3
- **Project period:** 2002-08-16 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247763

## Citation

> US National Institutes of Health, RePORTER application 10247763, Full Project 1: Understanding and Targeting of Convergent Immunosuppressive Pathways and Molecular Signaling in HPV-Positive and HPV-Negative Penile Cancer (3U54CA096297-17S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247763. Licensed CC0.

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