Navigating the Complex Mechanisms of HPV+ Head and Neck Cancers

Click the play button to listen now:

Subscribe: Apple Podcasts | Google Podcasts | Amazon Music | Spotify | iHeart Radio

Dr. Daniel Simon (Host): Hello, everyone. My name is Dr. Daniel Simon. I am your host of the Science at UH podcast, sponsored by the University Hospitals Research and Education Institute. This podcast series features University Hospitals' cutting edge research and innovations. Thank you for listening to another episode.

Today, I am happy to be joined by Professor Quintin Pan, Deputy Director of Research and the Dr. Lester E. Coleman, Jr. Chair in Cancer Research and Therapeutics at University Hospitals' Seidman Cancer Center. He is also the co-leader of the Molecular Oncology Program at the Case Comprehensive Cancer Center and Professor of Otolaryngology and Head and Neck Surgery at Case Western Reserve University School of Medicine. Welcome, Quintin.

Dr. Quintin Pan: Thank you, Dr. Simon. I am thrilled to be here today. I must admit, I am a bit over novice when it comes to social media. So please bear with me as I muddle through my first podcast.

Host: Great. Well, I can't wait to talk to you about HPV. And obviously, for our listeners, HPV is the name of a group of nearly 200 known viruses. They do not cause concerns in most people, but infection with some of the high-risk types is common and can cause cancer. Most people often associate HPV with cervical cancer, but head and neck cancer is really becoming a bigger issue. What is the impact of HPV on head and neck cancer? How are they related?

Dr. Quintin Pan: Right. So, let me go from the top here. So, you know, as you mentioned, HPV is a large family of viruses, some of which are low risk and some of which are high risk. The low-risk genotypes causes hyperproliferative diseases such as skin warts, but the problematic ones are the high-risk genotypes, which causes cancer. As you mentioned, most people associate HPV with cervical cancer. But as of 2022, the number of HPV-associated head and neck cancer cases were actually higher for the first time than HPV-positive cervical cancer cases. So, we're looking about 15,000 new cases for HPV-positive head and neck cancer compared to about 12,000 new cases for HPV-positive cervical cancer.

Now, the issue with the HPV-positive head and neck cancer is the upper trajectory of the disease is projected to continue to increase until about 2060. So, it is currently problem and it'll only become bigger for the next three to four decades.

Host: So, Quintin, we've learned a lot from the COVID experience that viruses are very elusive, they mutate, COVID vaccines work, then we need to update them, because there are new mutations that render our vaccines ineffective. So, tell us a little bit about the mutational frequency of HPV. And do you anticipate that HPV also will evolve over time and that, for instance, the vaccine Gardasil, which protects against HPV-driven cancers, may not be as effective if there's a mutation problem?

Dr. Quintin Pan: Right. So, the only HPV vaccine that's currently available in the US is Gardisil-9. It's a nanovalent vaccine and protects against nine different HPV genotypes, two low risk and seven high risk. This vaccine, or the HPV vaccines in general, were developed as a prophylactic to prevent against cervical cancer. Now, there is in level 1 evidence, a recent paper published from a European group to demonstrate that these HPV vaccines are highly effective to decrease the incidence rate of cervical cancer in vaccinated individuals versus non-vaccinated individuals. The expectation in our field is that the vaccines will also protect against HPV-positive head and neck cancer. This is an assumption, right? An educated guess. I'm an experimentalist and I completely rely on data and there is currently no experimental data to make this claim. And assumptions are dangerous, especially in the scientific space. And I certainly do believe that clinical trials are needed to either prove or disprove the notion that the HPV vaccine will protect against all HPV-related cancers beyond cervical cancer. So, we're not there yet. But I think as trials develop over the next few decades, we'll have an answer to this question.

Now, talking about mutational frequency in the HPV genome, based on available data, the HPV genome is quite stable and the mutational rates are not as varied as what we are experiencing with COVID. Now, with all that said, a lot of this work was done decades ago without using modern or contemporary sequencing approaches. So, I think there is a need to really apply our current technologies, especially deep sequencing, to better understand how the HPV genome can evolve over generations. Obviously, this is an ongoing work of high interest to the field, but certainly a very important research question that we need to address appropriately.

The concern that I do want to raise here is a concept called genotype replacement. So essentially, the replacement of HPV genotypes that are covered by the vaccine to genotypes that are not covered by the vaccine. This phenomenon of genotype replacement has been observed in pneumococcal vaccine where we are beginning to see an increase of non-vaccinated genotypes in that virus. As I mentioned earlier, HPV is a large family with hundreds of genotypes. The problem with genotype replacement is that the clinical responses and outcomes of these HPV genotypes are fairly distinct. Our research group made the initial discovery that HPV33 drives aggressive disease, whereas HPV16 drives a much more indolent disease. The risk of death in HPV33-positive patients was about two and a half times higher than the HPV16-positive patients. So, genotype does matter in the context of HPV-positive head and neck cancer and prognosis. The fear that I have is that the HPV landscape will evolve over time, especially in the face of these different HPV vaccines. And potentially, aggressive genotypes will replace indolent genotypes such as HPV16. So, we have to be careful. Certainly, a lot more work needs to be done to better understand the biology on why certain HPV genotypes drive aggressive disease.

Host: You know, that's very interesting and calls to mind that we know in pneumococcal vaccines that the number of strains goes up as they develop new vaccines. And so, the question is, with Gardasil affecting nine, will there be new HPV vaccines that cover 16 or 21 different variants? So, that's very interesting.

So, let's switch gears for a moment. Not a week goes by that we don't learn about a new personalized medicine approach to cancer, that there's a specific mutation that drives the cancer. And that we have now a selective drug, we see the commercials on TV, all the time for these drugs.

But I want to talk a little bit about HPV really as a cancer where we know about driver genes. And it seems that we still are treating these patients with standardized chemotherapy and radiation. Tell me, what has been the challenge to developing drugs for HPV-driven cancers? Are the genes involved different? Are the pathways different? Why are we sort of lagging in the head and neck cancer space?

Dr. Quintin Pan: Right, Dan, as you know, drug development is a very long game. It is a journey that expands decades and requires substantial financial investment often reaching of billions of dollars to transition an experimental drug from the bench to the bedside. The challenges of drug development in the HPV+ head and neck cancer space are multifaceted. First, this is a rare cancer, which means the return on investment for industry players, pharmas and biotechs, are not aligned with the resources required for extensive R&D efforts. Second, unlike other cancers that have well defined driver mutations, such as EGFR and ELK mutations in lung cancer or KRAS mutations in colon and pancreas cancers, HPV driven head and neck cancers present a unique challenge. We don’t have an established driver mutations to target in HPV+ head and neck cancers. This absence of defined targets complicates the development of molecular targeted therapeutics in this space.

Host: So, Quintin, you and your lab and Ted have been really focused on a very novel signaling pathway, which is that HPV causes cancer by blocking the signals such as p53 tumor suppression program that causes cells to die at the end of their natural life cycle. And as a result, these cells become immortal and continue to grow and divide, ultimately forming tumors.

So, your lab in collaboration with others at NYU has really identified some lead compounds that can stop HPV cancers by reactivating p53. It's really very exciting. Can you tell us about your programs in that? I know that you're already in early clinical trials, so it's very exciting.

Dr. Quintin Pan: Absolutely. So as you know, drug discovery does take a village, and I've been very fortunate to have a productive relationship with different synthetic chemists over the last few decades. One of my most productive relationship is with Bobby Aurora at New York University. He is a professor of chemistry and a world class synthetic chemist. So we really went into this work with a simple idea, “How can we reactivate tumor suppressive programs in HPV-positive disease?”

Now, what we know already is that HPV has two different oncogenes that dampens two distinct tumor suppressive programs in host cells. HPV E6 inactivates the tumor suppressive p53. And HPVE 7 inactivates Rb. Now, we also know, and this is work done by many groups over the last few decades, is that HPV E6 inactivates p53 through two distinct mechanisms. HPV E6 binds to host protein E6AP. And when this happens, it alters the conformation of E6AP, allowing it to interact with p53. E6AP then subsequently ubiquitinates p53 and shuttles p53 for degradation through the proteasome pathway.

The other mechanism that is less studied, but I think perhaps even more important is that HPV E6 interacts with the host protein P300. P300 can directly acetylate to control p53 functionality. It enhances p53 stability as well as transcriptional activity. And so, you know, when Bob and I started this work now, about 10 years ago, we wonder whether or not we can disrupt E6 p300 protein-protein interaction. So, our very simple concept is that if we can disrupt this protein-protein interaction, then we might be able to liberate p300 away from E6, allowing p300 to subsequently acetylate and reactivate p53 in the context of HPV+ cancer cells. And indeed, this did happen. So, we started with different genetic models. And working with Bobby's group at NYU, we started with a stable peptide to disrupt this E6 p300 protein-protein interaction. We subsequently transitioned to a first generation small molecule. And now, we have a second generation small molecule that is even more potent than our initial first generation drug. So, we are very excited and are in late phase preclinical development. And our hope is to bring this new molecule, this new drug, to the clinical space in 2025.

Now, this is sort of our novel drug discovery platform. And I do want to share two other drug discovery platforms that we are currently heavily invested in. One is, you know, as I mentioned, HPV E6 binds to E6AP. This facilitates the assembly of the E6/E6AP/p53 complex. This trimeric complex is also important to maintain p53 functionality in HPV+ tumor cells. The challenge with this trimeric complex is that the structure has not been solved. So, numerous groups have published structure using truncated proteins and small peptides, but the full length trimeric structure has not been solved due to various technical challenges that we don't really have time to touch on today.

But what's really exciting is our work with Derek Taylor, he's a structural biologist at Case. And working with this group, we now have this full-length trimeric complex resolved down to 2.6 angstroms, which will allow us to better understand how this complex assembles so we can design ways to disrupt this assembly, right? So, very early phase in terms of the drug development pathway, but what we think, you know, with the structure in place, we have a very, very exciting platform that will come up in the next few years.

One more point that I would like to highlight is our innovative drug repurposing platform tailored for HPV-positive cancers. Drug repurposing is the art of finding new indications for existing FDA approved drugs. In essence, this is a shortcut this to compress the lengthy drug development process. We identified an old drug, fenofibrate, that showed remarkable activity against HPV+ cancers. It is as active as current standard of care therapies in this space, Cisplatin and anti-pd1 antibodies, in various preclinical HPV+ cancer model systems. Based on our extensive work with fenofibrate, we are moving this drug straight to the clinical space. Our R&D for fenofibrate in cancer patients was approved by the FDA in Q3 of 2023. Looking ahead this year, we are planning two separate phase I window-of-opportunity clinical trials for fenofibrate. The first trial targeting HPV+ cervical cancer will be open in Q1 to Q2 of this year with Dr. Lindsay Ferguson as the clinical PI and Dr. Wendy O’Neil as the translational PI.

The second trial focusing on HPV+ head and neck cancers is set to follow shortly thereafter. These trials represent a pivotal step forward to bring innovative therapies to benefit our cancer patients.

Host: Quintin, it's incredibly exciting that you have sort of two different approaches, you know, novel drug discovery from crystal structure, but then using this repurposing path to be able to have a quick into-the-clinic. And obviously, it's so great to end our conversation that all comes back to the heart, because fenofibrate is a great drug that we use to treat elevated triglycerides in our patients with hyperlipidemia. So, finally, the cardiologist gets to say something here today.

Well, listen, I want to thank you so much for taking time to speak with us today, Dr. Pan. It's been a pleasure. I learned a lot from you and we are so lucky that Ted recruited you to be his Deputy Director for Research at the Seidman Cancer Center.

To learn more about research at University Hospitals, please visit UHhospitals.org/uhresearch.

Thank you very much for joining us today.