It’s less than 200 years since a German-Czech monk named Gregor Mendel pioneered what we now know as the science of genetics. In 2003, over 90% of the human blueprint was finally revealed when the human genome was sequenced, described by the Human Genome Project as “one of the most ambitious and important scientific endeavors in human history.”

We now know more about prostate cancer (PCa) genes than ever before, though not 100%. The search to cure metastatic PCa is one of the main drivers for research in the area of how gene activity may affect PCa treatment outcomes. As noted by Yehya, et al. (2022), “Multiple drugs are now approved as the standard of care treatments for patients with mCRPC that have been shown to prolong survival. Although the majority of patients will respond initially, primary and secondary resistance to these therapies make mCRPC an incurable disease.”^[i]

Metastatic disease is fearsome because a) at best, current treatments that add months to life come with the cost of unpleasant side effects, and b) spread to skeletal areas—a preferred PCa location—is agonizingly painful. Existing therapies target the androgen receptor pathway in order to deprive the PCa cells of testosterone (essentially, a form of castration), but most PCa cells eventually become castration resistant.

How do metastatic PCa cells develop this resistance so that treatment fails? A main theory suggests various gene mechanisms manipulate—and therefore govern—the androgen receptor pathway at the molecular level. Thus, development of new drugs is based on targeting this pathway. The problem is, not all patients respond equally to new drugs like Xtandi (enzalutamide). As one UroToday article puts it, “Perhaps the most significant clinical challenge today is deciding which type of treatment will work best for different prostate cancer patient groups.”

To that end, a multicenter, multinational team of researchers conducted a deep molecular analysis of single PCa populations developed resistance to Xtandi.^[ii] They identified cells with pre-existing gene expression patterns suggesting they behave like stem cells with regenerative properties, giving them the ability to survive androgen deprivation. This allows them to overcome the lethal impact of Xtandi. Thus, “The researchers’ results suggest that the presence of such patterns in cancer tissue may predict the risk of recurrence and disease development. Such information can help tailor treatment for different subgroups of prostate cancer patients.”^[iii] To gain information requires pre-treatment genomic analysis.

Implications for localized Prostate Cancer

Although the above study focused on castration-resistant PCa that has spread to remote areas of the body, it has implications for all PCa patients and for matching treatments to their disease. Learning more about the various lines of PCa cells and biomarkers to detect gene mutations that govern cancer cell behavior can help in three important ways:

1. It may account for cancer recurrence after whole-gland treatments that were apparently successful, e.g., radical prostatectomy specimens that look like “We got all the cancer,” and yet a few years down the road the patient’s PSA begins to rise.
2. It suggests future directions for developing inexpensive genomic analysis that can identify which patient has death-defying cellular properties that can threaten the patient’s own life, thus informing aggressive treatment strategies.
3. It guides the development of new immunotherapies and even gene therapies to target the mechanisms of gene expression that foster regenerative cancer cells.

There is good reason to be optimistic that laboratory research with cancer cells will lead to mastery over the mysterious ways by which treatments unexpectedly fail. There is good reason to anticipate that someday we will have the key to conquer prostate cancer, even in cases where it has invaded not just the gland but other areas in the patient’s body.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Yehya A, Ghamlouche F, Zahwe A, Zeid Y, Wakimian K, Mukherji D, Abou-Kheir W. Drug resistance in metastatic castration-resistant prostate cancer: an update on the status quo. Cancer Drug Resist. 2022 Jun 22;5(3):667-690
[ii] Taavitsainen S, Engedal N, Cao S, Handle F et al. Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse. Nat Commun. 2021 Sep 6;12(1):5307.
[iii] Popularized: Discovered Gene Patterns Can Predict Prostate Cancer Treatment Response – Beyond the Abstract.” UroToday, Nov. 16, 2021. https://www.urotoday.com/recent-abstracts/urologic-oncology/prostate cancer/133834-popularized-discovered-gene-patterns-can-predict-prostate-cancer-treatment-response-beyond the-abstract.html