Researchers with the University of Cincinnati and Johns Hopkins Medicine developed a potential treatment for brain cancer that uses nanofibers embedded with a combination of drugs that work in concert to target tumors.

The drugs proved more effective in combination than when administered alone and can provide both immediate and long-lasting doses to kill cancer cells.

Lead author Daewoo Han, an assistant professor in UC’s College of Engineering and Applied Science, and UC Distinguished Research Professor Andrew Steckl incorporated the drugs into electrospun fiber membranes, creating a nanofiber drug delivery system. Steckl’s NanoLab at the University of Cincinnati is a leading developer of this technology that uses an electric field to create a multilayered fiber mesh for drug delivery, among other uses.

“This combination is pretty powerful,” Steckl said.

Glioblastoma is the most common and aggressive form of brain cancer in adults. Researchers at UC and Johns Hopkins found that the three federally approved drugs used to treat glioblastoma (temozolomide, acriflavine and PT2385) work better in combination than they would alone, a pharmaceutical phenomenon called synergism.

“When you add them together, three things can happen,” Steckl said. “The combination is negative; the effect is additive, like one plus one equals two; or it’s synergistic, which is like one plus one equals three.”

The study was published in the journal ACS Biomaterials Science & Engineering. The research was supported with a grant from the National Institutes of Health.

Steckl said glioblastoma is extremely difficult to treat because its heterogeneous cells allow for mutations that help the cancer evade treatment.

“It’s tough to control,” Steckl said. “It comes in through the window and when you close the window, it comes through the door. And when you close that, it comes through the chimney.”

Glioblastoma also has high recurrence. And the blood-brain barrier limits the effectiveness of other traditional chemotherapies.

“Our NanoMesh system was designed to solve these issues by enabling localized long-term delivery of multiple synergistic drugs directly at the tumor site after surgery,” UC’s Han said.

UC researchers worked with a team at Johns Hopkins Medicine, including Betty Tyler, a professor of neurosurgery, and postdoctoral researcher Hasan Slika. Tyler said researchers are looking to attack the disease with combinations of therapies.

“Unfortunately, cancers know how to pivot to evade therapeutic treatment,” she said. “So we’re approaching treatment multidimensionally.”

Tyler has helped develop other cutting-edge therapies now commonly used to treat cancer.

“Current therapies have increased patient survival and given them more birthdays,” she said. “But we’re still working on improving options.”

In animal trials, all untreated mice with glioblastoma died within 19 days. But a majority of mice treated with the three-layer nanofiber mesh survived twice as long. And 40% survived past the 120-day conclusion of the experiment in a plateau that stretched for more than 80 days.

Han said using electrospun fiber mesh, doctors can precisely control the dosage and release and the implant geometry, which contribute to its effectiveness. And just as the blood-brain barrier protects the brain from toxins, the barrier also protects the body from the toxic side effects of the medicine applied to the brain, Han said.

UC researchers are now working on optimizing the long-term release of medicines using advanced nanofiber structures. And the delivery system has broad potential in applications for other difficult-to-treat diseases, Han said.

“What’s next will be very exciting,” Han said. “Our ultimate goal is moving forward to a clinically translatable system that improves both survival and quality of life for patients with difficult-to-treat cancers, including glioblastoma.”

Journal

ACS Biomaterials Science & Engineering

Funder

NIH/National Institutes of Health

DOI

10.1021/acsbiomaterials.5c01482

Prostate cancer remains one of the most pervasive malignancies affecting men globally. While initial treatment modalities often involve androgen deprivation therapy (ADT) to suppress AR signaling, many patients eventually progress to CRPC. This advanced stage of the disease is characterized by unabated tumor growth despite low circulating androgen levels, a resistance primarily attributed to the persistent activity of both full-length androgen receptors (AR-FL) and splice variants of AR (AR-Vs) that lack dependence on androgens. Understanding how these receptors sustain their activity in the absence of hormones is pivotal for developing next-generation targeted therapies.

The team’s study elucidates that a critical co-factor in sustaining AR activity is PCNA, a well-recognized DNA clamp that facilitates DNA replication and repair. Intriguingly, PCNA also interacts with AR, enabling efficient AR-mediated transcriptional activation. Through detailed biochemical studies, the researchers identified a second PCNA-interacting protein (PIP) box within the AR’s DNA binding domain, designated PIP-box592. This motif significantly enhances the binding affinity of AR-FL to PCNA, particularly when androgen dihydrotestosterone (DHT) is present, albeit such enhancement is absent in constitutively active AR splice variants like AR-V7.

Capitalizing on this discovery, Lu and Dong engineered a cell-permeable peptide, termed R9-AR-PIP, which mimics the identified PIP-box592 domain in AR, effectively acting as a decoy to disrupt the AR-PCNA interaction. Administering R9-AR-PIP to various prostate cancer cell lines, including androgen-dependent LNCaP cells and multiple CRPC cell lines expressing different AR isoforms, significantly reduced AR’s capacity to bind to DNA. This blockade resulted in a marked downregulation of AR target genes critical for cancer cell survival and proliferation.

Complementing the peptide approach, the researchers also evaluated a small molecule inhibitor, PCNA-I1S, known to impede PCNA’s nuclear translocation and its protein-protein interactions. Treatment with PCNA-I1S phenocopied the effects of R9-AR-PIP by attenuating AR activity and suppressing the proliferation of CRPC cells. These findings collectively support a dual modality to target the AR-PCNA axis, offering alternative therapeutic angles for intervention.

Among the most striking results was the observation that both R9-AR-PIP and PCNA-I1S treatments substantially diminished the levels of cyclin A2, a pivotal regulator of the S phase in the cell cycle. Cyclin A2 overexpression is commonly noted in aggressive prostate tumors and correlates with poor clinical outcomes. By curtailing cyclin A2, this therapeutic strategy not only impairs the proliferative capacity of tumor cells but also potentially sensitizes them to other therapeutic modalities.

The mechanistic underpinnings of these interventions reveal a nuanced interplay between androgen stimulation, AR structural domains, and PCNA co-factors. DHT’s ability to augment full-length AR’s interaction with PCNA hints at a complex regulation of AR activity that can be pharmacologically exploited. Meanwhile, the lack of DHT modulation for AR variants emphasizes the heterogeneity of CRPC and the necessity for multifaceted targeting strategies.

Importantly, this research addresses a longstanding challenge in CRPC therapeutics: the effective inhibition of AR splice variants that drive resistance to conventional anti-androgen therapies. By focusing on the conserved AR-PCNA interaction, the R9-AR-PIP peptide and PCNA-I1S small molecule provide promising avenues to overcome the limitations imposed by AR variant-driven resistance mechanisms.

The translational potential of these findings is significant. While current standards leverage androgen suppression and AR antagonists, the eventual emergence of resistant clones diminishes long-term efficacy. The inhibition of AR-PCNA interaction introduces a novel vulnerability, one that directly intersects with the molecular machinery protecting genomic integrity in tumor cells. This dual impact on transcriptional regulation and DNA replication stress may culminate in synthetic lethality, selectively eliminating cancer cells.

Looking forward, the authors emphasize the importance of validating these findings in in vivo models and clinical settings. The pharmacodynamics, bioavailability, and potential off-target effects of these agents warrant rigorous examination. Nonetheless, the study opens vistas for developing combinatorial regimens wherein AR-PCNA interaction inhibitors are combined with existing therapies to delay or prevent the onset of resistance.

Furthermore, this work enriches the broader understanding of how non-traditional functions of DNA repair proteins can be co-opted by oncogenic signaling pathways. PCNA, classically confined to replication and repair, is emerging as a multifunctional scaffold modulating transcription factor activity. Such insights may pave the way for analogous strategies in other malignancies where similar protein interactions drive disease progression.

The implications for personalized medicine are profound. Identifying patients with tumors heavily reliant on AR-PCNA interactions could inform stratified therapeutic approaches, leveraging peptide or small molecule inhibitors tailored to individual molecular profiles. This precision oncology paradigm underscores the necessity of integrating molecular diagnostics with therapeutic innovation.

In summary, the study by Lu and Dong constitutes a seminal step toward the development of innovative therapeutics in castration-resistant prostate cancer. By targeting the AR-PCNA interface—a hitherto underexplored axis—they offer hope for improved outcomes in a patient population with notoriously limited options. As this research progresses from bench to bedside, it represents a promising beacon in the fight against lethal prostate cancer.

Subject of Research: Cells

Article Title: Targeting PCNA/AR interaction inhibits AR-mediated signaling in castration resistant prostate cancer cells

News Publication Date: 20-May-2025

Web References:

• Journal: Oncotarget
• DOI: 10.18632/oncotarget.28722

Image Credits: Copyright: © 2025 Lu and Dong. Distributed under the Creative Commons Attribution License (CC BY 4.0).

Keywords: cancer, PCNA, androgen receptor, PCNA inhibitors, AR splicing variants, CRPC