September is National Prostate Cancer Awareness Month, a time to raise awareness of prostate cancer and the importance of research aimed at preventing the disease, detecting it earlier and developing more effective treatments.

According to the NIH’s National Cancer Institute, an estimated 333,830 new cases of prostate cancer are expected this year with approximately 36,320 deaths from the disease, making it the most diagnosed cancer among men in the United States. While many prostate cancers are discovered before they have spread beyond the prostate and have very high five-year relative survival rates, metastatic disease remains much more difficult to treat. An estimated 9% of prostate cancers are diagnosed after they have spread to distant parts of the body, where the five-year relative survival is about 40%.

The risk of prostate cancer increases with age, and having a close family member with prostate cancer or certain inherited genetic changes can also increase risk. Prostate cancer also disproportionately affects Black men, who experience higher rates of both diagnosis and death from the disease than other racial and ethnic groups in the United States.

Because prostate cancer can behave very differently from one person to another, researchers continue to work toward better ways to distinguish cancers that are likely to remain localized from those that are more likely to become aggressive or spread.

At the University of Cincinnati Cancer Center, researchers are approaching this challenge across the disease continuum — from preventing cancer from becoming invasive to understanding metastatic disease and developing new strategies for treatment-resistant cancer.

Understanding What Makes Prostate Cancer Progress

For Amar Natarajan, PhD, a senior advisor at the Cancer Center, one of the central challenges in advanced prostate cancer research is understanding what happens when cancer spreads beyond the prostate.

“Bone is the predominant metastatic site among advanced prostate cancer patients as it creates distinctive tumor–stromal, metabolic and immune interactions that can protect cancer cells from treatment,” Natarajan explained. “An area of interest is to dissect these microenvironmental resistance mechanisms.”

Amar Natarajan, PhD Senior Advisor University of Cincinnati Cancer Center

When prostate cancer spreads to bone, cancer cells interact with the surrounding environment —normal cells, signaling molecules and metabolic processes — in ways that can influence how the cancer grows and responds to treatment. Understanding these interactions, known as the tumor microenvironment, may reveal why some cancer cells survive treatment and provide new opportunities for targeting metastatic disease.

This work is part of a larger national effort to understand why prostate cancer becomes resistant to therapies that initially control the disease. Prostate cancer research is increasingly moving toward approaches that can identify vulnerabilities that were previously difficult to target and provide more detailed information about how an individual patient's cancer is changing.

“New technologies and research strategies, including PROTACs, molecular glues, covalent inhibitors, multi-omics, liquid biopsies and artificial intelligence-based biomarkers, are creating opportunities to identify previously inaccessible therapeutic targets, monitor emerging treatment resistance and potentially match patients with treatments based on the biology of their disease,” shared Natarajan.

Researchers are also examining how prostate cancer changes its identity as it progresses. Androgen signaling plays a central role in prostate cancer biology, which is why therapies that block androgen production or interfere with the androgen receptor are foundational treatments for advanced disease. However, some cancers eventually adapt and continue growing despite these therapies.

“Understanding and reversing androgen-receptor resistance and lineage plasticity — the ability of cancer cells to change their biological characteristics — has become an important area of research,” said Natarajan. “In some cases, prostate cancer can transition toward androgen-receptor-independent or neuroendocrine states that require different treatment strategies.”

At the same time, researchers are looking earlier in the disease process.

“Cancer prevention and interception, aimed at stopping progression before invasive or metastatic disease develops, is also emerging as a national trend,” Natarajan said.

This concept of cancer interception represents an important shift: rather than waiting for cancer to become invasive and then treating it, researchers are investigating whether the biological processes that allow cancer to progress can be interrupted before the disease reaches that stage.

Prostate Cancer Research at the University of Cincinnati Cancer Center

At the University of Cincinnati Cancer Center, research spans the prostate cancer continuum, including cancer prevention, mechanisms of disease progression and therapeutic resistance, drug discovery and clinical translation. Together, these efforts address different stages of the disease — from understanding how prostate cancer becomes invasive to developing treatments for patients whose cancer has already spread or become resistant to therapy.

Clinical trials help bring these discoveries from the laboratory to patients. One example is the Phase 3 KLK2-PASenger trial, which is aiming to evaluate whether adding the investigational therapy pasritamig to docetaxel can delay disease progression compared with docetaxel alone in patients with metastatic castration-resistant prostate cancer. Pasritamig is designed to engage T cells and target human kallikrein 2 (KLK2), a protein associated with prostate cancer. The study is designed to determine whether the combination improves radiographic progression-free survival.

The Cancer Center is also participating in research examining whether treating the prostate tumor itself can benefit patients whose cancer has already spread. This Phase 3 trial compares standard systemic therapy alone with systemic therapy combined with definitive treatment — surgery or radiation — directed at the primary prostate tumor in patients with metastatic prostate cancer. The study is designed to determine whether adding definitive treatment can improve outcomes in this setting.

Both led by Robert Franklin, MD, these trials reflect the breadth of prostate cancer research at the University of Cincinnati Cancer Center, from investigating new ways to engage the immune system against advanced disease to evaluating how local and systemic treatments can be combined.

Robert Franklin, MD Member, Experimental Therapeutics Research Program University of Cincinnati Cancer Center

Exploring New Ways to Prevent Prostate Cancer Progression

While much prostate cancer research focuses on treating established disease, Natarajan is also part of a collaborative effort exploring a fundamentally different question: Can prostate cancer progression be stopped before the cancer becomes invasive?

As a collaboration between researchers at the Cancer Center, Stony Brook University and the University of Nebraska, the NCI-funded project “Preventing Invasive Prostate Cancer” is investigating whether cancer cell motility — the ability of cancer cells to move through surrounding tissue — can be selectively inhibited to prevent prostate cancer from progressing from an in situ state to invasive disease.

“This project is evaluating KBU2046, a first-in-class compound designed to inhibit cancer cell motility,” shared Natarajan. “We are also studying how KBU2046 interacts with the HSP90β–CDC37–Raf1 protein complex and testing its effects in clinically relevant prostate cancer models.”

The premise is straightforward but potentially transformative: if cancer cells need to move in order to invade surrounding tissue, preventing that movement could provide an opportunity to intervene before invasive cancer develops.

Rather than treating cancer after it has invaded or spread, this approach asks whether a specific biological step in cancer progression can be interrupted earlier.

“If successful, it could introduce a new prevention-interception strategy, identify additional therapeutic targets and provide a framework applicable to prostate as well as other types of cancer,” Natarajan said.

The KBU2046 program complements other prostate cancer research at the Cancer Center, including studies of metastatic progression, tumor microenvironment, RON signaling, therapeutic resistance and advanced treatments, such as PARP- and PSMA-directed approaches. Together, these efforts reflect the Cancer Center's designation of prostate cancer as a priority hormone-related cancer and demonstrate how research can address different stages of the disease.

“The KBU2046 research is particularly distinctive because it asks whether prostate cancer can be pharmacologically intercepted before it becomes invasive — potentially establishing cell motility as a new therapeutic strategy with applications beyond prostate cancer,” explained Natarajan.

As researchers continue to understand the biology of prostate cancer at increasingly detailed levels, the goal is not simply to develop more treatments after cancer has progressed. It is also to identify opportunities to intervene earlier, prevent progression and tailor treatment to the biology of each patient's disease.

During Prostate Cancer Awareness Month, these efforts underscore the importance of research across the entire cancer continuum — from preventing invasion to understanding metastasis and developing new strategies for patients whose disease has become resistant to treatment.