Prostate cancer models are difficult to create; plus the potential of PARP inhibitors, CAR-Ts, and vaccines. Challenges and promise in prostate cancer research

Prostate cancer is one of the most common cancers found in men. Although usually the prognosis for prostate cancer patients is good, its widespread diagnosis makes it an important area of research. In honor of Prostate Cancer Awareness Month, Charles River research scientist William Durham from Morrisville answered some questions for a “state of the research” snapshot on this common cancer.

Problem: Prostate cancer models are difficult to create

“You have to take this from our point of view from our site,” said Durham. “From our point of view one of the most difficult things about prostate cancer compared with all the other histotypes we look at is the dearth of models. The majority of prostate preclinical studies has been conducted with just three human cell lines: DU-145, PC-3 and LNCap. It’s very difficult to develop a new prostate model whether from human or mouse tissue.”

According to Durham, prostate cancer has a complex disease heterogeneity and as a consequence prostate cancer models exhibit poor growth, poor take rate, and are prone to inconsistencies. Within the same study, some tumors for these models will grow perfectly, while others in the same group won’t grow at all.

Prostate cancer is progressive and has many stages, each of which can have several variants. For example, prostate cancer can be androgen dependent, or not, and metastatic, or not. That is four variants with only one type of prostate cancer.

Additionally, prostate tumors can exhibit multiple mechanisms of late stage resistance. These mechanisms can be due to androgen dependent and independent mechanisms which would require different preclinical models.

Potential treatment: PARP inhibitors

Long a favorite for treating breast cancer, poly (ADP-ribose) polymerase (PARP) inhibitors are showing promise for prostate cancer as well. Essentially, PARP inhibitors can block DNA repair that is essential for cells to survive by causing breaks in both DNA strands. Since cancer cells replicate more quickly than normal cells, PARP inhibitors can kill cancer cells more quickly than they can damage normal cells. With targeted approaches, the damage to normal cells can be further contained.

“If you can inhibit the proteins involved in repairing in the tumor cells, then the tumors will die,” said Durham. “They’ve been using this with breast cancer with BRCA mutations, and it turns out some types of prostate cancer have BRCA 2 mutations.”

Potential treatment: CAR-T therapy

In layman’s terms, chimeric antigen receptor T (CAR-T) cell therapy is when a patient’s own T cells are modified to attack cancer cells. The definition is simple and the therapy is promising, but the reality of the treatment complex.

“I think the biggest area that you’re going to see a lot more research for in the next few years is CAR-T therapies,” said Durham. “Really it is amazing stuff when they get it right. A lot of technical science is involved that can affect potency – it needs to be potent and it needs to hit the target, but it can’t be too potent or it will damage normal tissues.”

Despite the technical trickery that makes CAR-T difficult, Durham thinks the benefits are worth the trouble.

“The nice thing about T cells is if they are not activated, they can sit there for a long time until they’re needed,” Durham said. “If the tumor comes back, they could jump back into action. If they figure out the scientific difficulties associated with [CAR-T], it could be an extremely effective treatment.”

Potential treatment: Vaccines

Cancer treatment vaccines are a type of immunotherapy. The vaccines are designed to boost the immune system’s ability to recognize and destroy tumor-specific antigens while sparing healthy cells that do not possess the antigen.

Some tumor vaccines can be made for individual patients by collecting a sample of the tumor to create the vaccine. Other vaccines are designed to target a specific antigen, and are given to patients whose tumors possess those antigens on their surface.  

“There is a vaccine, sipuleucel-T, that was approved by the FDA in 2010 to treat patients with metastatic, hormone-refractory prostate cancer,” Durham said. “While this agent improves survival times, I think the problem with this therapy is that it doesn’t shrink tumors. I don’t believe our site has tested any vaccines designed to treat prostate cancer.”