Michigan Team Finds a Way to Attack Prostate Cancer That Has Changed Its Identity

About one in eight men will be diagnosed with prostate cancer, and in the US it is the second leading cause of cancer-related death among men. Most prostate tumours initially resemble prostate gland cells and depend on androgens — male hormones such as testosterone — for their growth, which is why androgen receptor inhibitor drugs are a mainstay of treatment for metastatic prostate cancer. These drugs can work well at first, but nearly all patients eventually develop resistance.

Some resistant tumours survive by activating alternative pathways that reshape the identity of their cells, a process scientists call transdifferentiation: the cancer cells lose some of their glandular characteristics and take on other cellular identities. Earlier research had linked the loss of two genes, TP53 and RB1, to this transformation, though why losing them causes such a dramatic change had remained unclear.

In a new study published in JCI Insight, researchers at the University of Michigan examined several prostate cancer cell lines to see which pathways changed when TP53 and RB1 were missing. "We saw that there are two sides to this transition: loss of glandular genes and activation of cell programs that cause the identity to switch into stem cells," said Joshi Alumkal, professor of internal medicine-haematology/oncology and a member of the university's Rogel Cancer Center.

The team had previously shown that BET bromodomain inhibitor drugs could weaken the pathway driving this alternative identity, but alone they did not kill the cancer cells. Adding DNA methyltransferase (DNMT) inhibitors — already FDA-approved for other conditions including blood cancer, and able to reactivate genes that had been switched off — suppressed tumour growth more than either drug alone, in cell lines and in mice. "When we used both drugs, we reversed a significant portion of gene expression changes that occur in the tumors, which is encouraging," said Will Storck, a research lab specialist in the Alumkal lab, adding that the combination worked even at doses far lower than the recommended dose.

The researchers now want to identify biomarkers that could show which patients are most likely to benefit from the combination, and hope to develop clinical trials to test it in patients whose tumours have undergone transdifferentiation.