Treating AR-Indifferent Prostate Cancer

Ana Aparicio, MD

Ahead of the ASCO-sponsored 2017 Genitourinary Cancers Symposium being held February 16th to February 18th in Orlando, Florida, we are today speaking with Ana Aparicio, an oncologist at the MD Anderson Cancer Center in Houston, Texas who specializes in genitourinary cancers. At the symposium, Dr. Aparicio will be giving a talk on advanced prostate cancer, titled “Advances in the Understanding and Treatment of AR-Indifferent Disease”

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: First, as background, can you describe the importance of the androgen receptor [AR] and its signaling in driving prostate cancer.

Dr. Aparicio: We have known for decades that the androgen receptor is at the center of most prostate cancers. We know that when we withdraw the ligand of the andrgeon receptor, prostate cancer cells die and tumor sites shrink. So there was, initially, when we would withdraw androgens, eventually resistance emerged and for many years we thought that these were then hormone-independent tumors. But in fact, in recent years, we’ve realized that the androgen receptor remains at the center of a large proportion of the prostate cancers that progress in the setting of low levels of the ligand, low circulating levels of the ligand, testosterone. So, it is of critical importance in prostate cancer.

OncoTherapy Network: So, you mentioned androgen withdrawal. Could you map out what the current androgen receptor-targeted therapies are for prostate cancer patients?

Dr. Aparicio: Sure. Basically, you can classify them into two major categories. Basically, the way that the androgen receptor works is that it is a protein and it is in the cytoplasm, bound to other proteins and its ligands are testosterone and dihydrotestosterone. Testosterone is present in the circulation and enters the cancer cell, is converted to dihydrotestosterone and when testosterone or dihydrotestosterone binds to the androgen receptor, there is a conformational change where it is released and it enters the nucleus where it now binds to androgen response elements on the DNA which elicit a transcriptional program of proliferation and survival. And so, you can target this pathway in two main mechanisms.

On the one hand, you can target the androgen receptor itself, so we have androgen receptor inhibitors and the current ones available will bind to the ligand-binding domain of the protein and compete with the existing testosterone and dihydrotestosterone, but have an inhibitory effect on the protein. So, there is a large list of such androgen receptor inhibitors, the initial ones were flutamide, bicalutamide, nilutamide, and more recently, the FDA-approved enzalutamide a more potent androgen receptor inhibitor. And there are a couple of other ones in development such as apalutamide.

The other way you can target the androgen receptor pathway is by going after the ligand, so going after the production of androgens, testosterone, and dihydrotestosterone. And that has been done in two ways. On the one hand, testosterone is fundamentally produced in the testicles and so you can use LH agonists or antagonists that will basically inhibit, they inhibit the production of testicular androgens, testosterone, so that depletes the circulating testosterone. As we learned in more recent years, you have castration resistance to these drugs and there are multiple mechanisms that lead to castration resistance, but one of them, for example, is the intratumoral production of androgens and so that is where the steroidogenesis inhibitors come in. For years, we used ketoconazole, an antifungal drug that had as a side effect, the inhibition of steroids and it was used in the treatment of prostate cancer and again, more recently, we have the development of a more potent and more specific steroidogenesis inhibitor, abiraterone. So that is the other main way we can target this pathway.

OncoTherapy Network: So what you refer to as androgen receptor-indifferent disease, is that known to come about only through drug exposure, so acquired resistance or are there cases where the prostate tumor is not dependent on androgen receptor signaling at the onset, so even before exposure to therapy?

Dr. Aparicio: So that’s a great question and very debated. So, what is the evidence, even, that there is anything like AR-indifferent disease? We have several clinical and preclinical pieces of evidence that I will discuss during my talk. But basically, one can start with the existence of androgen receptor-negative prostate cancer variants which do occur at diagnosis, although rarely.

So one such variance is small cell prostate carcinoma or neuroendocrine carcinoma which, more often than not, androgen receptor-negative. Now, the difficultly comes from the fact that a lot of times, these androgen receptor-negative, or tumors that do not express androgen receptor, that is what I mean here, as far as we can tell, those are often mixed with elements that do express the androgen receptor. So, it is not that the androgen receptor is completely absent from that tumor. But, so let’s assume the small cell prostate tumors are androgen receptor-negative tumors. And as I said, you do find them at initial diagnosis, there are primary small cell carcinomas that are rare, but do exist. And then there is the observation that in the castration-resistant progression of the disease, you have small cell prostate carcinoma elements, you find them often. In autopsy series, even before we had these more potent AR inhibitor strategies, we would find small cell prostate carcinoma elements in about 10% to 20% of the men dying of castration-resistant disease.

Now, so you could argue that, because these emerge, if you will, in the castration-resistant setting, you could argue that they might be a result of castration. But, we have seen that there are a number, and I should clarify that when we talk about small cell carcinoma, it is a morphological definition. It is something that the pathologist tells you that they see under the microscope and we know that that is disease that is associated with atypical clinical behavior in that it doesn’t do the usual bone-homing, bone forming metastasis that typical prostate cancer does, but rather often goes to the viscera and produces lytic bone disease and just has a very aggressive course and does not respond well to AR-directed therapies, but responds well to platinum-based chemotherapies.

We saw that a number of people who had these atypical clinical features, and we did biopsies to see if the patients needed platinum-based chemotherapy. So we started taking biopsies of a lot of these lesions and we found that a lot of times they didn’t have small cell carcinoma morphology on the biopsy and that they even might have expression of AR and yet clinically they behave very much like small cell carcinomas of the prostate. So we asked, ok, if you just have the clinical features, even if you don’t have the morphology, is that enough to predict benefit from platinum-based chemotherapy? And we did a phase II study and indeed we saw that there is a high response to platinum-based chemotherapy in men selected based on clinical features associated with small cell carcinoma. So, it was clinical behavior and not the morphology that predicted the benefit from the platinum chemotherapy. And when we looked to see whether these tumors also shared the molecular profile of small cell carcinoma, which is distinct from the typical adenocarcinomas and we asked whether the clinically defined aggressive variant cancers also shared these molecular features of the small cell prostate carcinomas. And indeed they did, and we came up with a signature which basically consisted of combined tumor suppressor defects, in p54, RB, and p10, so if you had two of those three that would qualify as an aggressive variant, molecularly. And recently, there have been two papers in Science that have modeled this, that in fact p53 and RB loss results in lineage plasticity and loss of dependence on the androgen receptor pathway.

I can tell you that there are, so while these mechanisms of AR indifference may emerge as a result of secondary resistance, there are a subset of men who we believe present with the underlying biology that will lead to this small cell type of aggressive variant behavior characterized by the loss of p53 and RB. So, are they AR indifferent from the beginning? Maybe not, maybe there is some participation of AR in their biology and progression, but our thought, and we are gathering data to support this, but our thought is that there is an underlying biology that predisposes for the emergence of very rapid AR-indifferent state.

OncoTherapy Network: Thank you so much for joining us today, Dr. Aparicio.