Uncovering how prostate cancer outsmarts treatment

Prostate cancer is heterogeneous: it is a hodgepodge of different kinds of cells, some worse than others. This often means the cancer becomes resistant to therapy – but sometimes, this change opens a new avenue of treatment that wasn’t there before.

In a recent study, published in NPJ Precision Oncology, through genetic analysis Johns Hopkins investigators closely followed the evolution of one man’s metastatic prostate cancer over more than seven years of treatment, looking for mechanisms by which his cancer became resistant to various therapies. The man was diagnosed at age 76 with a very high PSA (5,786 ng/ml) and widely metastatic, high-grade (Gleason 9) cancer.

To track the cancer’s complex evolution, medical oncologist Laura Sena, the study’s senior investigator, and her team sought the help of biomedical engineer Rachel Karchin and her team, who are experts in genetic analyses of tumor evolution.

“We determined that the patient’s original primary tumor contained two separate types of prostate cancer,” says Sena. “Although the dominant type of prostate cancer was effectively treated by the first approaches, unfortunately, the patient was not cured because the less dominant type of prostate cancer persisted, grew, and eventually spread widely.”

The initial dominant type of prostate cancer was a rare subtype with mismatch repair deficiency. Because of this, the patient was treated on a clinical trial with an immune checkpoint-inhibiting drug, nivolumab. At first, he responded well, with his PSA dropping down to only only 1 ng/ml, and scans showing a marked decrease in tumor volume. But over the next four months, his PSA began to rise. “Enzalutamide was then added to nivolumab treatment, which resulted in a sustained response over several years. Then, unfortunately, the cancer began to progress.”

This study, while documenting the patient’s cancer, shows the dedication and resourcefulness of his Hopkins oncology team, who never gave up. It also highlights the variety of drugs now available to men with metastatic prostate cancer. Next, the patient was treated with more chemotherapy, bipolar androgen therapy, a second trial of enzalutamide, and nivolumab in combination with ipilimumab, “without notable response to any agent.”

At this point, genetic analysis of a biopsy of an enlarged cervical lymph node revealed a surprise: a mutation in his BRCA2 gene. Using PictographPlus software, developed in the Karchin Lab by postdoctoral fellow Jiaying Lai, the genetics of this lymph node were compared with the original tumor samples. “Dr. Lai demonstrated that this mutation was present in a small portion of the primary tumor at diagnosis,” says Sena. Like tiny bad apples that go on to spoil the whole bushel, over seven years the cancer cells with this mutation expanded to become the dominant cancer type.

“Fortunately, recognizing this evolution of his cancer enabled him to receive treatment with a targeted medication that inhibits a molecule called PARP, which was highly effective,” says Dr. Sena. “This case provides evidence that therapy resistance can occur due to a process called selection, whereby a small population of resistant cancer cells are present before therapy begins. Cancer progresses despite treatment as these resistant cells grow and spread.” Dr. Sena’s laboratory is now focusing on “new strategies to prevent therapy resistance, in light of this new knowledge.”

This article originally appeared in the Brady Urological Institute’s 2026 Discovery Magazine >>