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Andrea Miyahira: Hi, everyone. I'm Andrea Miyahira here at the Prostate Cancer Foundation. I'm so pleased to be joined by Dr. Nicole Mavingire of Morehouse School of Medicine to discuss her paper, Revisiting HER2 in Prostate Cancer from an Inclusive Perspective: From Biomarkers to Omics. This was recently published in Cancers. Dr. Mavingire, thanks for joining us.

Nicole Mavingire: Thanks so much for having me. I am super excited to talk to you a bit about our paper. We're very proud of this paper, and it's a collaboration between Morehouse School of Medicine, Texas Tech, and University of Alabama at Birmingham.

So, the first issue we addressed in our paper is that prostate cancer is a major health problem. By 2040, PC incidence could reach 9 million cases per year being diagnosed. And currently, we know that one in every eight men will develop prostate cancer in their lifetime.

For Black men, we actually know this number is one in six, and Black men are twice as likely to die from the disease. And when we investigated five-year survival rates, it's a well-known statistic that when prostate cancer is diagnosed locally, survival rates after five years are almost 100%. But unfortunately, if it's diagnosed in a metastatic stage, your chances of survival drop to 36.6%.

One of the key contributors to these statistics is the inherent heterogeneity of the disease. And this happens on several levels. So first, there's heterogeneity among patients, where we can see that primary tumors and metastatic tumors will differ between different patients. But even within the same patient, their prostate tumors can be different. And then at the cellular level, the prostate cells may be different. And then at the genomic level, certain mutations can lead to the same genes being different in the cancer cells versus normal.

And lastly, the way that genes are regulated by acetylation or methylation is also different between normal and prostate cancer cells. And so we are proposing that these unique biological characteristics between patients, between normal cells, and between prostate cancer cells are all considered in a personalized medicine approach when evaluating HER2 in prostate cancer.

So what is HER2? Well, HER2 is part of a family of RTKs. There are four of them, and these receptors are found on the surfaces of epithelial cells, both normal and cancer. And HER2 is often dimerized with itself—it forms a homodimer—or it can dimerize with other members of the HER family as well as other receptors, which I won't go into quite yet.

In normal cells, we know that a finite amount of HER2 controls cell growth and proliferation. However, in cancer cells, the cells make more HER2, either by amplifying the gene ERBB2 or by overexpressing the protein on the cell surface, which makes the cancer cells grow much faster, and they can also metastasize to other areas.

This process has been most evaluated in breast cancer and has led to the discovery of HER2 antibodies, different inhibitors, as well as antibody-drug conjugates. However, it has also been noticed that these drugs and this pattern exist in other forms of cancer.

So, the first thing we noticed in our review was that HER2 plays a role in breast, lung, brain, and gastric cancers, which you can see shown here. And we noticed that previously, researchers had hoped that HER2 would be a straightforward, credible target for prostate cancer, similar to how it was in breast cancer. But we noticed that hasn't happened. And so the purpose of this review was to investigate why that is.

One of the first things that we noticed in our analysis is that we found that HER2 overexpression is driven primarily by ERBB2 amplification in breast cancer. And furthermore, we noticed that in the clinic, HER2 screenings often involve two processes: FISH and immunohistochemistry. FISH tests for the amplification, and immunohistochemistry tests for the protein overexpression.

So our analysis confirmed that in breast cancer, HER2 overexpression is driven by HER2 amplification. And we also confirmed that in prostate cancer, which is this small column here, amplifications are significantly lower, so it's more of a rare event in prostate cancer. This was confirmed by the study that we address in our paper. Other researchers have tried to test by fluorescence in situ hybridization (FISH) and noticed that it is a rare event, while even immunohistochemical staining has given a wide range of expression levels of HER2 in prostate cancer.

However, we do believe certain patients may still benefit from using anti-HER2 agents because studies have shown that even having HER2 at a low level is associated with a more aggressive tumor subtype, rapid disease progression, and poor survival outcomes. And we've also found that modifying common IHC core scoring systems—so breast cancer is the most common scoring system—modifying that scoring system specifically for prostate cancer could actually lead to more prostate cancer samples being shown to be HER2 positive, particularly in Black men.

So our paper also reviewed the state of traditional prostate cancer markers, of which we know the most common is PSA. However, it's not very specific for prostate cancer, which often leads to false positives and unnecessary biopsies for patients. And so in the clinic, they're now looking at other PSA metrics and additional markers, other prostate-specific markers, of which one of the most common is PSMA, which is only expressed in prostate cancer, not in benign prostate tissue.

But they're also looking at other markers. So the other marker we addressed in the paper is androgen receptor (AR). The androgen receptor is a well-established driver of the disease, and many papers have shown that certain AR mutations have been implicated in development of metastatic castration-resistant prostate cancer.

Furthermore, ADT, which is the most common treatment for blocking androgen signaling, is the most effective treatment that we have right now for primary prostate cancer diagnoses or primary prostate cancer patients. However, we do know that up to 50% of patients may eventually become resistant to ADT, and when their cancers become metastatic, they need to go on a different therapeutic. And so we thought, what about HER2?

To gain a more complete picture of HER2’s role in prostate cancer, we turned to an in silico form of omics technologies using Pathway Studio. And what it does is it takes genomics data, transcriptomics data, and proteomics data, and then it allows us to examine the molecular landscape of prostate cancer by layering these different levels on top of each other.

We were able to create networks and see different interactions that are happening with HER2, and possibly determine signaling mechanisms behind how HER2 works in prostate cancer. So one of the first networks we drew up was an interaction between HER2 and other major receptors—that's why they all have this same shape.

HER2 is— I mean, there are so many you can choose from, but NOTCH sticks out here, CXCR4 sticks out here. These two are both involved in metastasis. And then there are a lot of ITG receptors. Those are called integrin alpha or integrin beta. They're integrins, and they're involved in cell motility. So again, metastasis. So this opens the door for people to look into different signaling mechanisms that affect metastasis in prostate cancer.

We also looked at transcription factors and microRNAs, because these two factors regulate gene expression. And we found MYC, one of the most famous onco-transcription factors. There's also STAT3, which is involved in cell growth and cell proliferation. So again, this is confirming HER2’s oncogenic role and why targeting HER2 might be a good strategy for prostate cancer.

And then one of the last ones we did was to look at specific protein families. So the same way I said HER2 is part of a family, these different symbols here represent different protein families that researchers may want to look into to also further parse into the mechanism that HER2 is using in prostate cancer.

And so our ultimate goal is to show that HER2 can serve as a druggable prognostic biomarker for certain prostate cancer patients. And we believe personalized medicine is the best way to determine which patients will benefit from HER2 therapies. HER2-targeted drugs may work for those who have specific HER2 mutations—so basically, like amplifications. And then also West African ancestry may play a role because our work, and one other group, have shown that African American men are more likely to express HER2.

And then other genomic features that are identified through omics. But if you don't put good quality data in, you don't get good quality data out, and the way you get better data is by increasing the diversity of the information. That's why our paper stresses the need for more diverse enrollment of study patients in clinical trials.

And the way we see precision medicine potentially working in the future is that diverse patients are taken from the population, and their diverse tumors are removed. And we can get different models by getting patient-derived cells, and by producing these different models and then going into omics, we can get a whole host of network information on signatures and pull out different biomarkers, including HER2.

And these different profiles could then be matched to data that already exists in translational research, or to novel data that is being created as we speak. And by matching these profiles, we see—or we hope—that patients can be stratified into particular groups for each therapy that would be most applicable to them. So the appropriate drug based on the matching would improve their chances of successful treatment and hopefully reduce the current health disparities that exist today.

So overall, we wanted to refocus on HER2 as a promising therapeutic and prognostic target for prostate cancer, while advocating for the integration of omics, as well as increased consideration for diverse patient populations and tumor heterogeneity in clinical trials and translational research. So with that, I would like to thank all the authors who contributed to this paper, especially my mentor Dr. Burnham, for her guidance. And I want to thank the foundation and UroToday for the work you do and for allowing me to have this discussion.

Andrea Miyahira: Well, thank you so much, Dr. Mavingire, for sharing this. So do you know if the prevalence of HER2 alterations changes during prostate cancer progression, for instance, CRPC versus primary disease?

Nicole Mavingire: Yes, we addressed it a little bit in the paper. It's not consistent. Each research group has found different things, but the vast majority have shown a correlation between increased HER2 expression as the disease becomes metastatic or progresses to more aggressive forms.

Andrea Miyahira: Do you know if the HER2 or ErbB pathway interacts with AR in prostate cancer?

Nicole Mavingire: We do know this. So we address it a little bit in our paper. But in more detail, one of the key interactions that HER2 has with AR is that they're both like growth factors signaling mechanisms. And what's interesting is, in the presence of HER2 signaling—let's say a patient is on ADT and we're trying to inhibit the androgen receptor. Even if you do that with ADT, HER2 signaling goes up. And HER2 can feed into the AR signaling pathway so that it's as if AR is not being inhibited at all.

And then both HER2 and AR feed into an even bigger pathway called PI3K-AKT-MAPK-mTOR. All of those growth factor receptors—they all—HER2 and AR—feed into those. And so again, if you inhibit AR with ADT, HER2 still offers a backup mechanism to bypass the progress we're making, which may be an explanation for why, when men become resistant to ADT, they end up becoming more metastatic because the HER2 becomes the more active pathway.

Andrea Miyahira: Thanks. And I guess, if we were to consider HER2 as a therapeutic target, have efforts been made to investigate the existing HER2-targeting agents in prostate cancer?

Nicole Mavingire: Yeah, I'm actually really excited—well, there's a prostate cancer trial that I just found out about. They're trying to enroll, and so they're still in the process. There's no data yet. It's in very early stages. But it's a VA-based project, and they're going to recruit primarily an African American cohort of men to treat them with ENHERTU, which is the third-generation anti-HER2 medication.

So I'm very excited. I cannot wait for that data to come out. They're going to treat them in a metastatic setting. So those are the men that really need it, and so I'm hopeful. Previous studies, from back in the '90s, didn't do a good job because the patients were not even HER2 positive. And we may not know this for a fact because the patient's information is de-identified, but in an era where DEI was not at the forefront, we can almost assume African American men were not really part of those studies either.

So it's a double whammy. Previous studies had primarily European ancestry patients, and the HER2 expression was low in those patients. And so that's why anti-HER2 medicines did not work in those previous studies. So I'm very excited for this current study that's coming out. And I can't wait to see what happens.

Andrea Miyahira: Thanks. And what are your next research steps?

Nicole Mavingire: Our next research steps are pretty exciting. In our paper, those networks that I showed you—how I talked about there's different targets that any researcher, if you're interested, can access and try to follow down—we're trying to validate some of those genes and proteins in our own cells, in our animal models, and in our spheroid models. So we're looking at MYC, BCL2, MAP kinase, all the big ones.

We're going to evaluate and see if we can validate the overexpression of those genes and proteins in our cells, 3D models, and our animal models. And probably the most exciting piece of information is that our animal model, which uses an MDA PDX panel of tumor tissues created by the late, great Dr. Navone, we're treating those with one first-, second-, and third-generation anti-HER2 drugs. And we are already seeing exciting tumor size differences after we treat, so we're really excited to publish that. Can't wait to share.

Andrea Miyahira: Thank you so much for sharing this with us today.

Nicole Mavingire: Thank you for asking. This has been amazing.