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Welcome to BIOTECH NATION !!! With understandable interviews requiring no background in science, BTN attracts a wide global audience. From everyday people looking for hope in treatments in development, to bioentrepreneurs interested in the experience of their fellow travelers, to venture capitalists looking for possibilities in cutting-edge breakthroughs, to scientists simply interested in the work of others, BioTech Nation is the voice of human endeavor, driving science to new realities for everyone. These interviews are drawn directly from the public radio program, "Tech Nation", which also can be heard in numerous global radio and podcasting venues.
Few pieces of news are more heart stopping than a diagnosis of cancer. As these diagnoses are most often as unexpected as they are unwelcome, it may serve us all to learn how new efforts in treating cancer are actually approached. Progress is a parallel path. It combines new insights into cancer's behavior with building more and better life sustaining treatments in response to what's been learned. Doctor Sean Bohen takes us to where that point meets for the 70% of breast cancers which shall be diagnosed this year, a projected 240,000 cases in total.
Dr. Moira Gunn:He also talks about the surprising crossover to prostate cancer. Doctor Bohen is the president and CEO of Olema Oncology. Doctor Bohen, welcome to the program.
Dr. Sean Bohen:Thank you, Moira. It's a pleasure to be here.
Dr. Moira Gunn:Now developing new cancer treatments are not simply about just making new shots in the dark about let's try this and that or the same kind of shots but slightly different. And the real progress in new cancer treatments depends upon learning more about cancer as well as developing new tools to deal with that. And now at Olima, you are primarily focused on cancer specific to women, and your foremost programs have been a particular type, ER positive, HER2 negative, and metastatic breast cancer. Now I think we all understand metastatic. It means the cancer cells can travel to other parts of your body, but what's ER positive and HER negative?
Dr. Sean Bohen:Yeah. So so, the the way that, breast cancer is categorized is is by looking at different proteins that are expressed in the cancer cells. And so ER and HER2 are 2 of those particular proteins. So, ER is an abbreviation for estrogen receptor. So, estrogen receptor positive means when you stain the tissue when you make the diagnosis, you see the presence of estrogen receptors.
Dr. Sean Bohen:What that also then means biologically, is that one of the drivers of the growth of those cancer cells is estrogen signaling through that estrogen receptor. This is an old used, commonly used pathway. Right? So, if we think about estrogen receptor, everyone has a familiar experience with how estrogen receptor causes breast cell growth and proliferation. And that is if you think of a young woman entering puberty.
Dr. Sean Bohen:And what happens then is the ovaries start to secrete estrogen, which is a hormone which circulates throughout the body. It goes to the estrogen receptor in the breast tissue and other tissues that are estrogen responsive. And the turning on of that receptor turns on the growth and proliferation of the breast cells. And in puberty, that's normal breast development of a girl turning into a young woman. What we're used to thinking of.
Dr. Sean Bohen:What happens in cancer and breast cancer, what happens in many cancers is that cancer cell hijacks a normal growth and proliferation signal and uses it to grow and proliferate inappropriately. And when that happens, one of the things you want to do to try to slow down the cancer or stop it is turn that signal back off. The other, the HER2 that you mentioned is exactly a different kind of growth signal. It's actually a thing called an epidermal growth factor receptor. And so in the kinds of cancer that we're talking about, that, expression is not present.
Dr. Sean Bohen:But in some cancers, it is present. And then for those cancers targeting her too similarly and turning off signal is used to try to control the cancer.
Dr. Moira Gunn:Now let me ask you this. Certainly, when I was a young woman and I reached puberty and, estrogen kicked in and I, you know, became a woman and I had children and all of that, I understand those estrogen receptors. But then as women mature, there's less estrogen, or don't the receptors go away or don't they?
Dr. Sean Bohen:The receptors do not go away, and it is absolutely true that there is less estrogen. Again, the common experience that people will point to with regard to that is menopause. Right? Menopause is the ovaries significantly reducing, although not necessarily completely stopping estrogen production. So, postmenopausal breast cancer still is often ER positive HER2 negative.
Dr. Sean Bohen:ER positive HER2 negative is the most common form of breast cancer. It's about 70% of breast cancer diagnoses. And realizing that the median age in the US of diagnosis for breast cancer is 62 years of age. So, many, many of the of the women diagnosed with breast cancer have the estrogen receptor and are also postmenopausal. But there are other sources of estrogen in the body, in addition to the ovaries.
Dr. Sean Bohen:For instance, the progestins, the male, typically considered male hormones that can be produced in the body, can be converted by enzymes in your body into estrogens. So that then remains one of the main sources of estrogen after that primary ovarian production has decreased in menopause.
Dr. Moira Gunn:And so with these cancers, these breast cancers, the cancers have gotten enthusiastic about those estrogen receptors again?
Dr. Sean Bohen:Yeah. Yeah. They've become they they they have. What will happen is there's this growth and proliferation signal. And, of course, in a normal cell, if we go back to that breast development and puberty example, the cell has other signals that come in that say, Okay, that's enough growth and proliferation.
Dr. Sean Bohen:This is when you're supposed to stop. You've reached a certain volume. You have enough contact with other cells. We're going to turn that down. Right?
Dr. Sean Bohen:And so it's a kind of checks and balances. It's a little bit of a foot on the gas with the estrogen receptor, a foot on the brake with some other, growth slowing or halting signals, that cancer keeps the foot on the gas and disables the brakes.
Dr. Moira Gunn:There you go.
Dr. Sean Bohen:And that's where you run into this situation of the of the the uninhibited, uncontrolled cellular growth and proliferation of the cancer.
Dr. Moira Gunn:And that becomes the tumor.
Dr. Sean Bohen:In in indeed.
Dr. Moira Gunn:That becomes the tumor. So let's talk about your lead compound, which is in phase 3, the final final phase. And I should say you're also working in earlier phases in combination with other treatments from Novartis and from Pfizer. But let's start with this most advanced, this phase 3, and your compound itself. I mean, I really like how your website described it.
Dr. Moira Gunn:The compound was developed to completely antagonize the estrogen receptor. Now that has an everyday English appeal. I mean, if you antagonize me, I'll finally just throw my hands up and go away. The but what does antagonize mean scientifically?
Dr. Sean Bohen:Right. So scientifically in this case, it means turn off completely. And and in in this case, what the estrogen receptor does molecularly is it turns on the expression of genes that produce proteins that promote the cellular growth and proliferation. Okay? And so what we do by binding our compound, which is called palzestrant, it binds to the estrogen receptor where estrogen would normally bind.
Dr. Sean Bohen:But instead of turning it into an active growth and proliferation signal, it locks it in an inactive conformation and just shuts it off completely. And that's our way of depriving the cancer cell of that ER mediated growth and growth depriving the cancer cell of that ER mediated growth and proliferation signal.
Dr. Moira Gunn:So that estrogen, which is driving this tumor in the cancerous condition, it can't get in because the estrogen receptor has been blocked.
Dr. Sean Bohen:Yeah. That's exactly right. So so it'll get into the cell, but but when it goes to the estrogen receptor itself, it will find the place where it binds is occupied. And occupied by palzestrant, which not only blocks the binding of the estrogen, but basically holds the receptor in an inactive conformation. Now, as the cancer advances, the cell gets even craftier about this.
Dr. Sean Bohen:And one of the most common mutations, okay, so a change in the protein that occurs as the breast cancer advances, is the cancer cell changes the estrogen receptor protein to turn it on without any estrogen being present. Oh.
Dr. Moira Gunn:Yeah. That's nasty.
Dr. Sean Bohen:Yeah. It is. It is. And that is the most common mechanism, whereby the cancer progresses again after the patient is treated with another class of drug called a CDK 4 6 inhibitor, plus a class of drug that decreases estrogen production. That's what today is given when you're first diagnosed.
Dr. Sean Bohen:It's quite effective. But patients eventually find that their disease progresses. And about half the time, if you go look at that progressing tumor, what you find is that that estrogen receptor has been turned on by a change in the protein. Here's the great thing though, palazestrin binds that form of the receptor too. And when it binds that form of the receptor, it pushes it back into the inactive confirmation, and again, starves the breast cancer cell of that growth and proliferation signal coming from the estrogen receptor.
Dr. Moira Gunn:Now you're in phase 3, that final phase. Tell us about that. Who is in it? What's the state of their cancer? How many people?
Dr. Moira Gunn:What's it like for the women in the trial? Would you like me to think of 72 more questions? Tell me, do you have enough questions there? We wanna know about this trial.
Dr. Sean Bohen:Right. No. So the phase it's very exciting for us to be in phase 3. And as you mentioned, Moira, this is the last this is the last phase of of developing a drug That leads to, of course, if the trial's positive, shows a benefit for patients, that leads to being able to file an application with, with the regulatory authorities, the FDA in the United States, and and then hopefully get approval and and and offer this therapy, to cancer patients more broadly. Obviously, the journey there takes a while.
Dr. Sean Bohen:Palzestrant has been has been used to treat more than 300, ER positive HER2 negative breast cancer patients to date. With very encouraging data, both as a monotherapy. Right? So, this isn't, this is a pill that you take one time daily. You don't go to an infusion center, you don't, it's not an IV medication.
Dr. Sean Bohen:You take a pill once a day. And so, one of the objectives is not only to slow the progression of the cancer, to keep it from coming back, but also to make sure that the patients taking this medicine have a nice quality of life. This is very important, right? You you want to enjoy, be able to enjoy and feel well, and so and so that's a nice property as well. The ongoing, phase 3 trial is called OPERA -01.
Dr. Sean Bohen:So the OPERA -01 trial will enroll patients who are considered second or third line of therapy. That means they got the standard first line therapy, and then their tumors progressed. And so, the patients will be randomized with half of the patients getting our antagonist therapy, which is an oral daily pill. And then, the other half will get the existing standard of care, which is 2 different classes of therapy. Some of them are oral daily pills, some are injections.
Dr. Sean Bohen:And then we'll follow those patients to see if and when their cancer then progresses again. So that's the primary endpoint of the trial. We believe this trial will read out our our kind of top line, read out will be in 2026.
Dr. Moira Gunn:Oh, wild.
Dr. Sean Bohen:It's enrolling right now. It's a it's a global trial, all over the world. So the the combination that, we're most focused on is, with CDK 46 inhibitors. There there are 2 of those we've studied, one of which is from Pfizer. One of which is a Novartis drug.
Dr. Sean Bohen:And those are those are the drugs that are used in this first line setting. So what we're trying to do there is show that in the first line setting, when you're first diagnosed with metastatic breast cancer, that we can do better than the existing standard of care that targets estrogen, which is the aromatase inhibitor class. That drug class decreases estrogen production in the body, but it doesn't bind the estrogen receptor at all. The problem with that is when these changes arise that turn the receptor on, the aromatase inhibitors don't have any effect. So, with the Olima drug, palazestrant, we believe we're going to be able to stop that mechanism of resistance and progression by locking the receptor in an inactive confirmation, regardless of whether it has this change to make it estrogen independent or not.
Dr. Moira Gunn:Now I should say there's a lot more to what Olima is doing. You have efforts in other types of breast cancer, in endometrial cancer, and even in prostate cancer. You know, from what we've talked about today, what is the commonality?
Dr. Sean Bohen:Yeah. So so the the that's such a fantastic question because the the the, the commonality is different in those different types of cancers. So so in the gynecological cancers of which, endometrial or or cervical cancer is an example, That those are also, as you'll appreciate, tissues where estrogen receptor is active in normal physiology. Right? And so, those tumors sometimes use the estrogen receptor growth and proliferation signal inappropriately as ER positive, breast cancer does.
Dr. Sean Bohen:So so we we haven't started the trials there yet, but we are examining how might we approach using a complete estrogen receptor antagonist to approach those gynecological cancers. And, the the the prostate cancer role is something a bit different. That's a different target. So we have a program that, we will enter the clinic late this year or early next toward a different type of target, and that's called CAT 6, katnumber6. And that is a protein that changes the structure of what's called the chromatin.
Dr. Sean Bohen:It's how the DNA is folded up in your cells. And it just so happens that the cat 6 chromatin modifying agent affects targets of hormone receptors. So, in the breast, it's the estrogen receptor. In the prostate, it's the androgen receptor. And so the overlap is because this, chromatin modifying agent actually interacts with both of these hormone receptors.
Dr. Moira Gunn:So it's good for every
Dr. Sean Bohen:I wouldn't quite go that far, but but
Dr. Moira Gunn:We hope so. I hope so.
Dr. Sean Bohen:It's, it is it is a fascinating intersection of biology. And in an ideal world, what we would be able to do because we know that our our that palzestrant estrogen receptor, antagonist combines well with other drugs. In an ideal world, we would find a way to combine it with cat 6 as well, and then give another new therapeutic option for, for patients with breast cancer.
Dr. Moira Gunn:So we've come back to the beginning and that we have we're learning more about cancer and we're developing new tools which feed right into what we are learning about cancer.
Dr. Sean Bohen:It's it's absolutely true that there is a that that that there is a somewhat iterative aspect of this. Right? That that you you find out, you know, estrogen receptor is actually an old cancer treatment target. Tamoxifen was approved in 1977. Right?
Dr. Sean Bohen:So so so the the concept that this was a way you could treat cancer has actually been around for quite a while and is very well demonstrated. But as you learn more about it, you say, well, we're making a difference. We're treating the cancer and having an effect, but we're learning that we're not doing quite as well as we possibly could. So, then you go in and you change your approach and you try something new. And that's how you get from tamoxifen, which does not completely turn off the estrogen receptor, to saying, okay, we want to turn it off completely now.
Dr. Sean Bohen:And so, you refine that approach. And and obviously, the objective is really straightforward, which is to is to keep people alive longer with high quality of life, and and and and be able to treat these cancers. And so that that's that's the end game here.
Dr. Moira Gunn:Now I learned something interesting about Olima when I was working on this interview. And, I have to say in in biotech, when we say, oh, we're a company from San Francisco, we're really saying South San Francisco. That's where the big cluster is, you know, of all these companies, you know, right there on the whole San Francisco Bay Area has many companies in it, but Right. It usually means South San Francisco. You're actually in San Francisco.
Dr. Moira Gunn:How can that be?
Dr. Sean Bohen:Yeah. We are. We are. There are few of us. We're we're not the only one, But, we, we are based in the city of San Francisco.
Dr. Sean Bohen:Our lab space is on Brannon Street. Our, our office space is on Owens, very near the UCSF, Mission Bay campus. And it's just, you know, for us, it's a very exciting place to be. Obviously, there's the Bay Area Biotech Hub, which is exciting. We, for instance, have clinical trials enrolling patients across the street, which is kind of exciting.
Dr. Sean Bohen:And, we do also I have to say you have to you have to acknowledge this as well. We also have a very important office in, Cambridge, Massachusetts. So we we get access to all the great talent and and knowledge in the in the Cambridge, Boston, biotech hub as well.
Dr. Moira Gunn:Well, I have to say you like your bio clusters.
Dr. Sean Bohen:Yep. We do.
Dr. Moira Gunn:You're right in the middle of those. Well, doctor Bohen this has really been terrific. I really appreciate, you coming in, and I hope you'll come back and keep us updated.
Dr. Sean Bohen:Oh, I would love to. I would love to provide an update. And thank you, Moira. It's it's just it's really exciting to get to share the story and the progress that we're making. And and and hopefully, when I come back, we'll talk about, you know, how there's a promising new therapy, for breast cancer patients.
Dr. Moira Gunn:Doctor Sean Bohen is the president and CEO of Olema Oncology. More information is available on the web at olema.com. That's olema.com.