Overcoming a new form of recognized resistance to modern prostate cancer drugs


Prostate cancer neuroendocrine cells. Credit: Dr. Aaron Udager, Michigan Medicine

Cancer cells have an incredible ability to evolve and adapt to overcome the treatments used against them.

While has been expanded with modern drugs that block the production or action of male hormones that feed prostate cancer — androgen receptor inhibitors such as enzalutamide, apalutamide, darolutamide, and abiraterone — and finally these medications stop working. At this time, a patient’s illness is considered incurable or what doctors call metastatic, .

In a new study, a team of researchers led by Joshi Alumkal, MD, who heads the prostate and genitourinary medical oncology section of the Rogel Cancer Center at the University of Michigan, discovered new mechanisms underlying a major type of resistance called lineage plasticity. It is then that castration-resistant prostate cancers go through a deadly change of identity, which goes from resembling glandular cells. , which can behave more like .

Results appear with human and mouse cell models and patient tissue biopsies Cancer clinical research and outline a promising path to overcoming this form of resistance: BET bromodomain inhibitors. These compounds work against bromodomain and extra-terminal proteins (BETs), which are involved in the regulation of gene activation.

“We know that emerging neuroendocrine prostate cancer treatment is becoming more common as we use newer, more potent androgen receptor inhibitors,” Alumkal said. “Our previous work examining patients progressing on these new androgen receptor inhibitors showed that neuroendocrine prostate cancer was found in 17% of cases. In comparison, we found it in less than 1% of patients. “Patients who have not undergone any form of androgen receptor inhibition. This strongly suggests that interference with androgen receptor function contributes to the increase in the number of neuroendocrine prostate cancers emerging from treatment that we now see clinically.” .

Patients diagnosed with neuroendocrine prostate cancer emerging from treatment are much worse than patients whose tumors remain adenocarcinomas (glandular tumors) that survive only about a third. In addition, there are very limited treatment options for patients with neuroendocrine prostate cancer emerging from treatment.

“We aimed to understand how tumors change their program to become neuroendocrine, the influence of androgen receptor inhibition in this process, and ways to block the shift to neuroendocrine prostate cancer,” said Alumkal, who he is also co-leader of the translational and clinical program. research program at the UM Rogel Cancer Center.

This line of research began when Alumkal was at the Knight Cancer Institute at Oregon Health & Science University and continued after his transfer to UM in 2019. The effort included a number of collaborators at other institutions, including scientists from the Dana-Farber Cancer Institute at Harvard University, the University of Washington, the Fred Hutchison Cancer Research Center, the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, and the Memorial Sloan Kettering Cancer Center.

A promising countermeasure

The main question the researchers tried to answer was whether modern prostate cancer drugs — the new and most potent androgen receptor inhibitors — could be as effective at turning off the androgen receptor in some tumors that these drugs could promote tumor change to become neuroendocrine. tumors.

And the answer seems to be yes.

Using a series of experiments using laboratory cell models that were sensitive to new androgen receptor inhibitors or their equivalent cell models with acquired resistance, the research team found that inhibition of androgen receptor accentuated a program of plasticity of the neuroendocrine prostate cancer lineage in resistant cells. unattainable effect on sensitive cells.

“Ultimately, we found that a critical difference that can allow resistant cells to react differently and become more neuroendocrine is due to the way their DNA is organized and packaged,” Alumkal said. . “In treatment-resistant cells, chromatin is organized in a more favorable way to activate this neuroendocrine program when the androgen receptor is blocked. It is as if the resistant cells have evolved to develop a hole of rabbit through which they could change their identity and inhibit the escape androgen receptor.We also found that high levels of a transcription factor called E2F1, which is involved in cell differentiation and stem, it is important “ability to change identity”.

And it was this work to discover the mechanisms that led to the emerging neuroendocrine cancer of the treatment that also pointed to a potential solution: BET inhibitors.

Although E2F1 cannot be targeted directly, the Alumkal team determined that E2F1 cooperated with BET bromodomain proteins to activate a neuroendocrine prostate cancer lineage plasticity program. Blockade of BET bromodomain proteins in cellular models stopped the activation of this program that drives the development of neuroendocrine prostate tumors, the research team found.

“When we treated a variety of emerging prostate cancer neuroendocrine cell lines for treatment with BET inhibitors, we significantly reduced the viability of these tumors, including patient-derived tumors,” Alumkal said.

The study is based on a previous clinical trial by Alumkal and colleagues, which found an inhibitor of the BET bromodomain inhibitor developed by Zenith Epigenetics, ZEN-3694, which appeared to be more active in castration-resistant prostate tumors. which had the lowest androgen receptor activity. In addition, trial patients whose tumors did not respond well to androgen receptor inhibitors prior to study enrollment appeared to have the longest-lasting control with ZEN-3694, suggesting that the most aggressive tumors they may be particularly susceptible to inhibition of BET bromodomain.

“We went back and determined that several patients in that ZEN-3694 clinical trial had neuroendocrine prostate cancer emerging from treatment,” Alumkal said. “When we examined the subset of those patients who did better, they had the highest expression of E2F1 and the bromodomain protein BET BRD4 and the lowest expression of the androgen receptor.”

“When we examined the plasticity program of the neuroendocrine prostate cancer lineage that we identified in our cell models, we found that these same genes were highly activated in the tumors of patients with emerging neuroendocrine prostate cancer who responded better. to treatment with ZEN-3694 “. added.

Ultimately, Alumkal said, research points to BET bromodomain inhibitors as potentially more beneficial for androgen-dependent prostate cancer patients and those with emerging neuroendocrine subsets of treatment. , especially tumors in which E2F1 transcription factor may be playing an important role.

Based on the findings of the current study, a larger international randomized clinical trial is being planned to evaluate the efficacy of ZEN-3694 with a particular focus on men whose tumors responded poorly to human receptor inhibitors. ‘androgens, tumors that may be less dependent on the receiver.

New clues as to why some metastatic prostate cancers do not respond to enzalutamide

More information:
Dae-Hwan Kim et al, BET Bromodomain Inhibition Blocks a AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Line, Cancer clinical research (2021). DOI: 10.1158 / 1078-0432.CCR-20-4968

Citation: Overcoming a Recently Recognized Form of Resistance to Modern Prostate Cancer Drugs (2021, June 18), retrieved June 19, 2021 at https://medicalxpress.com/news/2021-06-newly-resistance- modern-prostate-cancer.html

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