Subtype of Highly Aggressive Prostate Cancer Increasing; Tied to Drug Resistance to Hormone Therapy

2013-08-01 13:52:04

Novel drug being tested in multi-site Phase II clinical trial to treat men with this aggressive form of prostate cancer known as neuroendocrine prostate cancer

Cancer is a disease in which normal cells evolve and acquire the abnormal ability to grow in an uncontrolled fashion. That process of evolution, or change, that cancer cells undergo is not limited to the outset of malignant cancer, but often continues as the cancer progresses or is subjected to drugs or other therapies used to treat a cancer. This continuous process of cancer cell evolution inside a patient’s body is what allows cancer cells to become resistant to a drug or treatment. So while a treatment or chemotherapy may initially be effective at stopping cancer cell growth and shrinking tumor size or tumor bulk inside the body, eventually many malignant cancer cells evolve in crafty ways that allow them survive the persistent onslaught of drugs, or other treatment slings and arrows sent their way.

Currently there is a Catch-22 occurring in advanced prostate cancer treatment. Newly FDA-approved, highly potent, anti-androgen medications used to treat advanced prostate cancer have improved survival time in men with treatment-resistant prostate cancer; however, those very drugs may be inducing some men’s cancer to further evolve into a subtype of cancer called neuroendocrine prostate cancer that is highly lethal. (Androgens are male hormones such as testosterone that fuel prostate cancer growth.)

“The newer, second-generation anti-androgen drugs have really improved outcomes for prostate cancer patients overall,” says Dr. Himisha Beltran, medical oncologist at Weill Cornell Medical College specializing in the treatment of prostate cancer and a Prostate Cancer Foundation-funded researcher. “In general, these drugs extend life and improve symptoms; they’re great drugs,” says Beltran. “But, there is a potential mechanism of resistance,” she adds, referring to cancer cells that evolve in ways that ultimately make them immune to the effects of anti-androgen drugs.

Such drug resistance problems in cancer will likely never go away, but the trick is to develop drugs that delay resistance from developing for so long that malignant cancers can become a chronically managed disease rather than a death sentence.

And there is potential good news on the horizon for the treatment of neuroendocrine prostate cancer: a drug is currently in clinical trials for the treatment of neuroendocrine prostate cancer that has shown strong performance in pre-clinical testing.

What is neuroendocrine prostate cancer?

Over 90 % of malignant prostate cancers occur in the form of adenocarcinoma, which is characterized by uncontrolled growth of the prostate cells that secrete the prostate specific antigen (PSA). This is why many men with malignant adenocarcinoma of the prostate have elevated PSA levels. Generally adenocarcinoma is highly treatable with excellent cure rates, even though every prostate cancer of this type has the subtype neuroendocrine cancer cells scattered throughout the tumor. (Even benign, normal prostate glands have a tiny population, roughly about 0.1 %, of neuroendocrine cells, nested throughout the gland. See Figure One. It is thought these neuroendocrine cells normally play a role in early prostate development or perhaps function.)

The neuroendocrine cells scattered throughout adenocarcinoma of the prostate generally make up about 1% or less of the total tumor. Neuroendocrine prostate cancer (NEPC) is diagnosed when vast numbers of neuroendocrine cells are found in a tumor. “Neuroendocrine prostate cancer cells look small under the microscope,” says Dr. David Mulholland, of Mount Sinai Medical Center and a Prostate Cancer Foundation-funded researcher studying aggressive subtypes of prostate cancer. “And they tend to metastasize not just to bone, as is common in adenocarcinoma, but to liver or other abdominal visceral organs.” There are also a number of biochemical markers for NEPC that can be detected by tissue-staining lab tests, which aids in diagnosis of this disease.

Very rarely are men newly diagnosed with prostate cancer that is the neuroendocrine subtype. When this does occur it is called de novo NEPC, referring to the thought that this subtype of cancer has been there de novo, or from the beginning. Far more commonly, NEPC is a result of treatment with hormone therapy, and is known as treatment-related NEPC, or t-NEPC.

How does treatment-related NEPC differ from metastatic adenocarcinoma?

While the eventual development of resistance to anti-cancer drugs is universal in men with treatment-resistant prostate cancer, be it adenocarcinoma or NEPC, there are important differences between the two cancer types that may be very important in selecting the treatment given.

“What we’re learning [about treatment-resistant disease] is that when resistance develops the cancer cells are still androgen-receptor driven, in the majority of cases,” says Beltran. She is referring to the androgen receptor that binds with androgens such as testosterone to drive prostate cancer progression. This means that newer generation anti-androgen hormonal therapy drugs such as Zytiga (that blocks androgen production) or Xtandi (an androgen receptor (AR) inhibitor) have a good shot at extending these men’s lives. In fact, because they were shown to do just that, the FDA recently approved these drugs.

“However, in a small percentage of patients, their cancers can convert upon exposure to these drugs,” says Beltran. When that happens, when treatment with hormone therapy converts or transforms adenocarcinoma into NEPC a very important shift in the cancer’s biology occurs: NEPC are no longer dependent upon androgen or androgen receptor for their growth. That means that hormone therapy is unlikely to benefit these men. For men with NEPC, the prognosis is grim, with average survival times of less than one year.
NEPC cases on the rise

While NEPC is considered rare it is increasingly seen in the clinic say doctors. What’s more, because NEPC is an end-game state of the disease, it is most likely severely underdiagnosed. Most men who have late stage metastatic disease rarely undergo biopsy of their tumors once those tumors have spread to bone or soft tissue regions of the body. So while only 1 to 2% of prostate cancers are diagnosed originally as NEPC, many cases that develop after adenocarcinoma has evolved into NEPC go undetected. “We think about quarter of patients who are dying of prostate cancer are dying from treatment-related NEPC,” says Beltran.

Because NEPC is negative for the androgen receptor (AR) and because PSA is a target gene of AR, typically patients with NEPC have very low PSA levels in their blood. This can be very confusing to both patients and even doctors, says Beltran. “I see patient referrals that say: ‘history of prostate cancer; patient now presents with small-cell cancer of unknown origin,” she says. When PSA is nil or very low, it can be difficult to fathom they are dealing with a prostate cancer that has spread to the liver, she adds. “But when we do the molecular tests, we know it’s small-cell NEPC,” says Beltran.

Researchers seem to agree that hormone therapy against androgens and the androgen receptor wipes out the population of adenocarcinoma cells that are driven by AR, leaving a greater percentage of NEPC cells that do not rely on AR to grow to survive and thrive. But there is no certainty if neuroendocrine cells originally have the stem-like renewal quality that makes them so difficult to treat, or if that is part of the conversion process as hormone therapy is given over time. Mulholland tends to believe the former, Beltran the later. Adding some weight to the camp who believe that NEPC cells are clones, or descendants, of adenocarcinoma cells is the fact that about half of NEPC tumor cells have an aberrant genetic rearrangement commonly found in half the cases of adenocarcinoma.

And there are other factors that are likely important in the development of NEPC. For example, a paper published this spring in the Asian Journal of Andrology puts forth the idea that mutation of the P53 gene may be a critical event necessary for NEPC to develop. They provide some evidence that when P53 functions normally it is part of a pathway that keeps neuroendocrine cells in check, or in what is known as a quiescent state. But once P53 mutates, that control pathway is inactivated, and when this happens neuroendocrine cells run amok, growing wildly and behaving aggressively.

This spring Empire Genomics announced they are collaborating with Beltran and her mentor Dr. Mark Rubin to develop a clinical test for NEPC, which will greatly aid in better and earlier diagnosis of this deadly subtype of prostate cancer.

Early Detection and Treatment on the Horizon

A major advancement against NEPC came in 2011 with the publication of a paper in Cancer Discovery finding that two genes (Aurora kinase A and N-myc) were significantly overactive (overexpressed) in NEPC tumor samples. Additionally, the research, led by Beltran, showed that 40% of NEPC tumors had extra copies of these two genes, whereas only 5% of adenocarcinoma prostate cancers had extra copies. None of benign (normal) prostate tissue samples studies had extra copies of the genes.

This gave researchers a molecular marker that will aid in the diagnosis of this disease. And, even better, a drug is already well into development that inhibits the activity of Aurora kinase A. Currently an oral compound (MLN8237) that inhibits the activity of Aurora kinase A is already in clinical trials for other types of cancer, and Beltran and colleagues have just opened a Phase II clinical trial of the drug candidate in men with metastatic treatment-resistant prostate cancer whose cancers have evolved into the NEPC subtype. The trial opened in New York at Weill Cornell Medical College this spring, and Memorial Sloan-Kettering Cancer Center this summer and will soon extend to eight other cancer centers in the United States and one in the United Kingdom.

Preclinical results of aurora kinase inhibitors against this lethal subtype of prostate cancer showed great promise: in mice models of NEPC the drug dramatically shrank tumor mass—between 50% and 85%. Interestingly, the drug had virtually no effect on tumors predominately made up of adenocarcinoma cells. This lack of effect on adenocarcinoma cells would explain why prior studies of aurora kinase inhibitors failed against prostate cancer—the men in those studies likely did not have NEPC but rather treatment-resistant adenocarcinoma.

Researchers believe that Aurora kinase A and N-myc work in tandem to transform adenocarcinoma prostate cancer into the NEPC subtype. When Aurora kinase A mutates, becoming an oncogene that goes into overdrive, that in turn dysregulates N-myc, which drives adenocarcinoma cells to morph into NEPC cells that have stem-cell like qualities associated with rapid, uncontrolled growth. This domino-like chain of events in the development of NEPC means that inhibiting Aurora kinase A may likely be enough to halt the transformation process, which indirectly inhibits N-myc. The study in Cancer Discovery was the first to implicate N-myc in prostate cancer of any kind.

In fact, normally N-myc is silent, or not expressed, in prostate cells. Up-regulation of the N-myc gene is strongly associated with a form of pediatric brain cancer known as neuroblastoma, another highly aggressive neuroendocrine cancer. “The N-myc gene is a gene associated with brain development, and we need to understand what is corrupting the gene’s software, turning it on in prostate cancer cells so that we can put a halt to that malware,” says Dr. Jonathan Simons, the president and CEO of the Prostate Cancer Foundation. Simons adds that because N-myc overexpression is involved in other fast-growing, aggressive cancers such as certain pediatric brain tumors and T-cell lymphomas it may be time to stop thinking of NEPC as an organ-defined cancer, but rather a cancer defined by its molecular malfunction. Because this N-myc malfunction transcends prostate cancer, Simons thinks curing NEPC will require collaboration and data sharing among standardly discrete fields of research such as pediatric oncology, leukemia and lymphoma/hematology, and, of course, prostate cancer. “The idea is that we need to look across the landscape of other cancers that have malfunctioning N-myc for drug targets,” says Simons.

“Our clinical trial of this aurora kinase A inhibitor will be the first clinical trial of a targeted therapy against NEPC,” says Beltran. “And we’ll learn a lot along the way about NEPC because every patient in the study will undergo molecular profiling,” she said. Beltran says they have already learned, looking back at samples from primary prostate tumors taken from patients who later went on to develop NEPC, that around 60 to 70% of those early tumors had extra copies of Aurora kinase A and N-myc. “So if we could identify these men with extra copies of those two genes at diagnosis, then the hope is we could target their tumors with aurora kinase A inhibitors early in the disease process, before their adenocarcinomas transform to the very aggressive NEPC subtype of prostate cancer,” said Beltran. That might also mean avoiding treating such men—with a genetic predisposition to NEPC—with powerful anti-androgens, or at the very least, influence a closer surveillance program of their cancer.

Anti-Androgens--To Treat or not to Treat

The benefits of anti-androgen therapy outweigh the risks,” says Mulholland. “With treatment-resistant prostate cancer, you get an added five months of life,” he says. The fact that anti-androgens may later nudge some men with prostate cancer into the end-stage neuroendocrine subtype is just further motivation to personalize medical options for patients, he adds.

Beltran agrees wholeheartedly that precision medicine will ultimately be the solution. She is part of a Stand Up to Cancer-PCF Dream Team that will study tumor samples from men pre and post treatment with potent anti-androgen drugs, combing through their molecular signposts, looking for a NEPC signature. “We want to know, can we further identify men--based on their individual cancer type--who should get anti-androgen drugs, who will benefit the most, and the least, when is the optimal time for anti-androgens and when it is best to hold off on these drugs,” says Beltran.

And while cancer cells’ ability to develop resistance to drugs will continue to be a bane to men with aggressive forms of prostate cancer, every advance in therapeutics that lengthens time to drug resistance means that more and more men will be able to live a normal lifespan with their cancers, managing it as a chronic disease, not succumbing to it.