Introduction:

Penile squamous cell carcinoma (PSCC) is a rare malignancy representing <1% of male cancers in developed countries. Advanced PSCC carries poor outcomes: <50% of patients derive no benefit from first-line platinum chemotherapy, responses are typically short-lived, and there is no established second-line therapy. Clinical development of new agents has been limited by the rarity of PSCC and difficulty conducting adequately powered trials. Drug repurposing—the systematic evaluation of existing drugs for new indications—is particularly well suited to rare cancers like PSCC. This approach leverages compounds with known safety profiles, bypassing years of early-stage drug development and facilitating faster translation to the clinic. Transcriptomic signature reversal, which matches disease-specific gene expression profiles with compounds that can reverse these signatures, has successfully identified candidates in other rare diseases and cancers. We applied this strategy to PSCC to identify novel therapeutic opportunities.

Methods:

The NCBI Gene Expression Omnibus was queried using the terms penile cancer and penile squamous cell carcinoma, selecting studies profiling human tissue. Two public datasets were identified: GSE196978 (16 tumors and 6 normal glans) and GSE57955 (39 tumors and 5 normal glans). Differentially expressed genes (DEGs) were defined as those with absolute log2 fold-change > 1 and false discovery rate < 0.05. To identify candidate therapeutics, DEGs were filtered to include only landmark genes and submitted independently to the Broad Institute’s Connectivity Map (CMap) using Touchstone parameters. CMap compares disease-specific gene-expression signatures to >1 million perturbagen profiles to identify compounds predicted to reverse the tumor signature. FDA-approved compounds with a median normalized connectivity score ≤ –0.30 in both cohorts were considered reproducible hits. These compounds were annotated with primary targets and mechanisms of action via the Broad Repurposing Hub, and a targeted literature review assessed prior evaluation in PSCC.

Results:

A total of 59 compounds were identified as reproducible transcriptional reversers of PSCC tumor gene signatures across both datasets. Candidate drugs were classified into broad mechanisms of action (MOA) (Table 1). The largest categories were steroid/hormonal agents (14/59, 24%), antimicrobial/anti-infective agents (11/59, 19%), and neuropsychiatric/neurotransmitter modulators (11/59, 19%). Additional categories included cardiovascular drugs (6/59, 10%), classical chemotherapeutics or targeted oncology agents (5/59, 8%), immunomodulators/ anti‑inflammatory agents (5/59, 8%), membrane/cellular integrity disruptors (1/59, 2%), and miscellaneous compounds (3/59, 5%). Notably, none of the 59 candidates have been clinically evaluated in penile squamous cell carcinoma, with the exception of a single case report of sunitinib use in 6 patients with advanced disease. This underscores the translational gap between computationally predicted drug candidates and the current clinical landscape in PSCC.

Conclusion:

This study generated a focused list of 59 reproducible candidate compounds for potential drug repurposing in PSCC using transcriptomic signature reversal. Most compounds were steroid/hormonal, antimicrobial, or neuropsychiatric agents, reflecting the inflammatory and infectious transcriptional landscape of PSCC rather than direct antitumor activity. Notably, the analysis also identified classical chemotherapeutics, targeted kinase inhibitors, and select immunomodulators as biologically plausible leads for clinical translation. These findings provide a rationally prioritized starting point for rare‑cancer drug discovery, which historically lacks systematic repurposing pipelines. Next steps include preclinical validation in PSCC cell models and xenografts, evaluation of pharmacologic feasibility and safety, and integration of mechanistic filtering to triage the most promising agents toward trial‑ready repurposing opportunities. By combining computational screening with rational experimental follow‑up, this approach can accelerate the identification of actionable therapies in rare genitourinary malignancies.

Funding: N/A