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

Host: Today, I am happy to be joined by guest, Dr. Afshin Dowlati, who is the Lucile and Robert H. Gries Endowed Director of the Center for Cancer Drug Development, the Director of the thoracic Oncology Program, and the Director of the Phase I Drug Development Program at the Seidman Cancer Center. He is also a professor at the Case Western University School of Medicine.

Dr. Dowlati is a renowned oncologist and an expert in treating thoracic malignancies such as lung cancer and mesotheliomas. Welcome, Afshin.

Dr Afshin Dowlati: Thank you, Dan.

Host: So before we begin, tell me a little bit about yourself. Where did you grow up and train? What inspired you to be a physician scientist and an oncologist?

Dr Afshin Dowlati: Well, I grew up pretty much in many cities, including my initial home country, Iran, and Detroit, Philadelphia, Texas. I spent over a decade in Western Europe. And what brought me to the, University Hospitals is I did my medical school at the University of Liège in Belgium. And I specifically came to University Hospitals because of the training opportunity that was available for me in cancer drug development. We had some pretty renowned physician and scientists here at both University Hospitals and Case Western Reserve University, that really drew me to the education here. And then, I ultimately stayed to develop my own career.

Host: Terrific. So, you know, Afshin, we all turn to you for lung cancer. And lung cancer is the second most common cancer in both men and women in the United States, accounting for about one in five of all cancer deaths. I'm just a simple cardiologist, and there're different types of lung cancer, it gets a little bit confusing. We hear about small cell, non-small cell lung cancer, squamous cell, adenocarcinoma. What's related to smoking? What isn't? What's the difference between small cell and non-small cell? Help us for both the physician, but also for the patients.

Dr Afshin Dowlati: Absolutely. So, lung cancer is generally divided into two main categories. The first category, the most common, which is about 85% of all lung cancers, is what we call non-small cell lung cancer. And 15% is small cell lung cancer. This is the most common cause of cancer-related deaths. There's over 200,000 non-small cell lung cancer patients in this country a year, and there is about 20,000 to 30,000 small cell lung cancer patients. So, it's a very common disease. Now, non-small cell lung cancer being the more common one is a big category of itself. It has a lot of subcategories. That is an extensive one-page list. But the most common ones within the non-small cell categories are adenocarcinoma, squamous cell carcinoma and large cell carcinoma of the lung.

What's peculiar about non-small cell lung cancer is that, although it's much more frequent in patients that have smoked, obviously, you can even get it if you've never smoked. And up to 10-15% of the patients in this country who develop non-small cell lung cancer have actually never touched a cigarette. And so, it is a disease of smokers and more common smokers, but can happen in what we call never smokers as well.

So, the second big category of lung cancer is small cell lung cancer, which as I mentioned, is up to 15% of all lung cancers. Now, small cell lung cancer is a very peculiar disease. I always tell people there's two main characteristics for this cancer. Number one, it is one of the most fastest growing cancers we know amongst the solid tumors. It has a high propensity for early metastases. It spreads very rapidly to multiple organs and it's not uncommon for us to see the patient for the first time with metastases to the liver, adrenal glands, brains and bones. The second main characteristic of small cell lung cancer is that it tends to occur mainly in those who have smoked. Over 99% of the patients are patients who've smoked for many, many years. So as opposed to non-small cell lung cancer, where you can develop if you've smoked and even not smoked, but small cell lung cancer is really a disease of smokers, but it is quite still common, 20,000 to 30,000 cases a year in this country.

Host: So Afshin, obviously, cancer treatment is changing very, very rapidly. You turn on the television, you see commercials for Opdivo, Yervoy; immunotherapy has really taken over. Tell us a little bit about how these new therapies have impacted lung cancer and, in particular, lung cancer survival.

Dr Afshin Dowlati: Absolutely. So, I think lung cancer is one of those diseases where the improvements of therapy have been absolutely incredible over the past decade. It's extremely gratifying to see the therapeutic advances that we have seen in lung cancer over the past decade. So, most of those, however, are in non-small cell lung cancer. And what are these? They tend to fall into two big categories.

The first category of advances that we see in non-small cell lung cancer treatment are what we call genomically targeted. So, these are patients in which their tumors are sequenced, usually DNA or RNA and a specific genomic abnormality is identified, which is the driver oncogene or the driver of tumor growth. So, these driver oncogenes can be targeted, they can be blocked, they can be shut off, and it usually results in significant cancer regression in the majority of patients.

So over the past decade, we have identified at least nine specific targets in non-small cell lung cancer that we are able to target with specific many of these oral drugs, some of them kinase inhibitors that can shut down the oncogenic process, result in tumor regression and remissions. These include targets such as the EGFR, which is the most common in this category, epidermal growth factor receptor. But there's also other ones such as ALK rearrangements, ROS1, NTRK rearrangement, BRAF mutations, HER2 mutations, K R A s, mutations and a few others. So when we get a patient with non-small cell lung cancer, it is absolutely necessary that the tumor be sequenced by next generation sequencing, that we look for these specific genomic alterations. And if they're there, usually that will be our first line of treatment for treating lung cancer.

In those patients, again, all related to non-small cell lung cancer. Now, the second big category of advance in care of lung cancer has been in the immunotherapy realm that you mentioned. So immunotherapy, relates to drugs called checkpoint inhibitors. And there are really drugs that, result in the tumor being recognized by the immune system and the immune system going after the tumor.

Now, what's really interesting about immune therapy is that it tends to work, mostly in those who don't have those genomic abnormalities, so it allows a greater number of patients to be treated. And when you see a response to immunotherapy, I tell people it tends to be profound, dramatic, and many times of long duration.

So unlike chemotherapy, when we see responses and we see shrinkage of tumor in our patients, those responses tend to be. short-lived. They don't last very long, unfortunately. And that's one of the downsides to chemotherapy in most patients. Not in all but immunotherapy. When it works, you see these tumors shrink and then they go into remission.

They shrink. And the patient can stay in that state for quite a long time, if not many, many years. And what's really interesting in this particular setting is that if you look at the survival curves of patients with advanced non-small cell lung cancer, so stage four disease, Where previously you could not imagine many patients living five years now, you absolutely see 20 to 25% of the patients living five years and beyond in these survival curves have a plateau at the end of them, which is really, really exciting.

So both immunotherapy and genomically targeted treatments have revolutionized the treatment of non-small cell lung cancer.

Dr Dan Simon (Host): You know, I wanna thank you, Ashman. I don't, think I've ever done this. I'm getting a little choked up. Many years ago, I sent you my aunt, from Milwaukee who, had metastatic lung cancer. And, she did not have genetic testing. And you told me, get her here. And, we'll test her.

And it turns out she had an E G F R mutation. And, while her prognosis in Milwaukee was set to be in under six months, she lived over six years. So, I wanna thank you and your team for really changing people's lives and my family's life. So thank you very much. Now I have a question for you, because this is quite a title.

You're the director of Phase one Drug Development. Tell our listeners exactly what that means. I think, we know that there are clinical trials, and we think. Very much about phase two and phase three trials. We don't know a lot about investigator initiated trials and actually new drugs.

Tell us a little bit about this program, because I know it's your passion and you're leading that at the Simon Cancer Center.

Dr Afshin Dowlati: Absolutely. So in drug development, which is absolutely my passion, drugs that are developed in the laboratory, they're discovered by many different mechanisms in the laboratory. They go testing there to determine if they work in animal models, but ultimately, they shouldn't stay in the laboratory.

They need to come to human beings. We're here. To help improve patient's lives, improve survival, improve quality of life. So how do these drugs get to human beings? Well, they have to start somewhere, and it's usually in patients, with advanced cancer where new drugs that are being developed. Against that specific tumor are tested.

So patients are, interested in, discovering new drugs for their cancer. Usually their cancer is advanced. they have, received multiple lines of treatment. Um, I do not say the patient has failed the, the treatment, but actually the treatment has failed the patient and they're looking for newer therapies, something that may control their cancer.

And what is incredible is that we have the opportunity of bringing these new discoveries from the laboratory to patients, and that's what we call phase one clinical trials, intense studies. they are, Very highly monitored. We have to figure out what dose to give the patient. We have to slowly escalate the doses in different cohorts of patients, identify the side effects for the first time in patients, describe them very well, and ultimately our goal is to find the correct dose.

That is both tolerable and potentially has the chance of being efficacious in patients. And so it's a stepping stone for developing a new cancer drug. All the drugs we have right now, all of these good therapies that we talked about previously, ultimately have gone through phase one clinical trials and they have been shown to be both safe, and the doses have been figured out.

But also there have been signs of efficacy, and when that happens, they go on to phase two and phase three clinical trials.

Dr Dan Simon (Host): Well, that's really terrific and I think it's, just perfect that our new case, comprehensive Cancer Center director, Dr. Gary Schwartz, is also a, phase one drug, passion guy, and obviously in the very rare and difficult cancer space of sarcoma and osteosarcoma. So, Great to have a new, partner in that effort.

So you've been doing a lot of work recently, in small cell, lung cancer, and you have I think a new discovery of a novel therapeutic in small cell lung cancer. Can you tell us a little bit about that?

Dr Afshin Dowlati: Absolutely. So I have been working on small cell lung cancer for 20 years, and it's really. a passion of mine. It's something I think about, every single day. So, small cell lung cancer. We talked a little bit about the biology of a disease earlier on in this podcast. And, really no therapeutic advances unfortunately have occurred.

Until recently for this subgroup of lung cancer patients, small cell lung cancer. So what was discovered, recently is the fact that, well, maybe small cell lung cancer is just not one big disease, similar to non-small cell lung cancer where we now. Slice and dice into many different diseases with different genomic abnormalities, different driver oncogenes in small cell lung cancer.

We are also starting to discover different subtypes of small cell lung cancer. So what, my lab has discovered, along with my work at University hospitals has been a group of small cell lung cancers that just behave differently. And I noticed in my practice there's about 20% of small cell lung cancer patients.

When I give them chemotherapy, their cancer does not shrink. And so I was always bewildered by this question and always, try to figure out why are these 20% of patients not responding to chemotherapy? So being a physician scientist with one foot in the laboratory and one foot actually seeing patients, It allowed me to take those specimens, those biopsies from patients who were not responding.

We started sequencing them, from a genetic standpoint, and we discovered that the non-responders, those who do not respond to chemotherapy, are those who lack. An RB alteration. An RB stands for a retinoblastoma gene. So there's an RB one gene. Many people may have heard of RB one retinoblastoma, where alterations in it results in a childhood cancer known as retinoblastoma, which is a form of tumor within the children's eyes.

But retinoblastoma gene plays a critical role in small cell lung cancer. In previous to our discovery, it was felt that every single patient with small cell hadn't. Retinoblastoma gene alteration. What we found out is those 20% of patients who do not respond to chemotherapy are mainly those who lack in RB alteration i e.

They have what we call an RB wild type status. So going on from there, we ask ourselves, okay, if they're not respond to chemotherapy, what else is going on here? So in a recent publication, we demonstrated that these patients who are R B Y type. That 20% actually respond to immunotherapy. So we brought that checkpoint inhibitor, immunotherapy concept from non-small cell lung cancer to the small cell lung cancer.

Were, and recently demonstrated that the majority of people who respond to immunotherapy in the small cell lung cancer space are those who are r b wild type. But we didn't stop there. What was really interesting is when we did a whole bunch of laboratory experiments, And looked at, tumor models that were RB wildtype, meaning no alteration versus RB mutant.

We tested a whole bunch of drugs in the laboratory, one group versus the other. We found out that in the RB Wildtype category, a group of drugs known as CDK four six inhibitors. Seem to work. They do not work in the RB mutant, but they work in the RB wild type. So that really got us excited. Of course, this has to go through animal models and we went, did all that and we were able to demonstrate that these CDK four, six inhibitors work in these, RB wild type are non rb, non altered, cells and animals, and the result can be quite profound.

So what do we do afterwards? Being a drug development person that I am being a phase one person that I am, it's not enough for me to see something shrink a tumor in a mouse. I have to see it. Get to patients. So what we did is we launched a clinical trial here. an investigator initiated clinical trial here at University Hospitals using a CDK four six inhibitor called Abemaciclib in, patients with small cell lung cancer.

Who lack RB alterations are rb wild type. So it's a very difficult study to do, because again, we're talking about 20%, 10% of small cell lung cancers, but because of the amount of small cell lung cancer being really a, a. Reference center, a referral center for lung cancer, and in particular, small cell lung cancer.

We get referrals from everywhere, including, treated patients from Chicago, New York, and even further and beyond that. Come here for this, we launched this trial and it's in its accrual phase, but what was so important is the proof of principle that this works in humans. So our first patient that went on study.

Was a 55 year old African American woman who had what we call chemo refractory small cell lung cancer, meaning she did not respond to chemotherapy and she really had an orange size mass, on the side of her neck. And so because she had RB wild-type small cell, agreed to go on the study, consented, went on study, and within 30 days that, basically or in size mass disappeared.

In the first patient we gave this drug to. Now the study is ongoing, so we don't know exactly what percentage of patients, I can't give a percentage, but there is a proof of principle here that the laboratory discovery can easily be taken. To clinical work here at University Hospitals and directly benefit our patients with these novel therapeutics and novel clinical trials.

So the study's ongoing, but the result is so exciting, both the animal work and the human work that it was just recently published. So we're really, enthusiastic and happy about that.

Dr Dan Simon (Host): Well, that's really inspiring. And I have to say this is a walking commercial for our researchers hope, sentiment of university hospitals. Basic discovery work, translation, clinical trials, health services, research, all to bring patients hope, those who need the latest drug device or cell-based therapy, for a really tough problem.

Thank you so much Ashvin for joining us, today, to tell us all about your exciting work, in lung cancer. For our listeners interested in learning more about research at University hospitals, please visit. Uh, hospitals.org. Thank you.