Wall Street Doesn't Believe in This Target

"Wall Street doesn't believe in this target," by Dario Altieri. A scientist shares his 12-year journey that led to the discovery of a drug now in clinic.

TRANSCRIPT

Narrator: Wall Street Doesn't Believe in This Target by Dario C. Altieri, MD (10.1200/JCO.22.00180)

March 2, 2009. Just published in the Journal of Clinical Investigation.1 And we even got the cover. Twists and turns of heat shock protein-90 (Hsp90), the chaperone, the evolutionary capacitor. Great name and important cancer target. People smiled when I talked about this at the Hsp90 conference. No, no, really there is a lot of it in mitochondria, and only in mitochondria of tumor cells. And, I don't know why, but Hsp90 drugs don't touch it: somehow, they don't get to mitochondria. So, I made my own. Took an old Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin and attached it to triphenylphosphonium, a carrier that basically gets anything into the mitochondria. No, of course, I didn't do the synthesis in my laboratory. What do I know about medicinal chemistry? Outsourced it. Like sneakers and sweaters. And after three months, there it was: an Hsp90 inhibitor that only goes to the mitochondria, causes aggregation of a lot of proteins, and kills tumor cells in minutes. Makes sense, right? Mitochondria must control protein folding, especially in cancer, and they do it with chaperones. Inhibit the process and tumor cells can't cope. Normal cells don't seem to mind. So, strong preclinical activity, and against a lot of different tumor types. Better than any other Hsp90 inhibitor. Good safety. Totally different mechanism of action. And even a cool name, Gamitrinib.

Tired of curing mice. What if this were to work in people? Ideas are made in academia; drugs are made in companies. Okay, fine, then I'll launch a startup, spinout, whatever they are called. The (former) doctor-turned scientist now turns entrepreneur, and then captain of industry. Problem is, I am not like that. More like an (aged) boy scout. The inner soapbox says: it belongs to the American taxpayers; they funded it; it's theirs. Excellent start. What else? If doctors and scientists become businessmen (or businesswomen), who will take care of humanity and discover new things? Perfect for a campaign ad. Sold. Bring it to the patients solely from academia: no pharma, no biotech, no investors, no nothing. Soapbox meme for the day: Yes, we can. It's going to cost. So? I'll write a grant, that's what I do for a living anyway. And the fact that I know zero about drug discovery? Or drug development?

Laboratory-Clinical Transition Award from the Department of Defense. Great title. Three years of funding. Perfect for me. Pass-through money, nothing for the laboratory, but it pays the bills of outsourcing. First things first. Synthesize Good Laboratory Practice (GLP) Gamitrinib. Already getting a pretty good hang on the acronyms. Hey, we made this drug lots of times before and has never taken this long. It's almost a year and counting. The Department of Defense (DoD) is on my case because I am already behind. What's going on? Yes, I understand that we don't make anything in this country anymore. New import permits that need to clear the Indian government? The what? This is just a chemical, not an international incident. Yes, I get it, nothing I can do about it.

My new job is mailman. And telephone operator. Finally shipped the GLP drug for the toxicology. Two animal species, says the US Food and Drug Administration (FDA). Rats and dogs sound good to me. Should I feel sorry for the dogs? Rats not so much. But what if Gamitrinib poisons the mitochondria in the brains? Or hearts? Wait, you said it's just perfect? Animals are doing great, all of them. And no toxicity at all, like giving them…water. Wow, that's some news. Feeling quite pleased with myself. See? I said it all along: mitochondria are wired differently in cancer. That's why the drug is safe for normal tissues. Maybe I should write a review article about that. Serious boost of the citation index. I am sorry, what? Yes, of course I know that the drug is purple. Okay, you filtered it before giving it to the animals and instead of purple it turned white? And you did that to all animals. For the entire time. Oh, what do I think it means? I think it means that you filtered out the drug and we have been giving animals…water. Yes, I get it. I need a new formulation. And start over. Note to self: find a new Contract Research Organization (CRO) that doesn't give water to the animals.

Formulation experts. Big pharma ex-pats who now have their own CRO. Everybody is an entrepreneur here. Is this drug oral? Nope. Is it soluble in water? Not at all. So, it's an intravenous (IV) infusion? Yes, that's what it is. Sorry, then it's not a drug. It's not? And what about things like, you know, paclitaxel or doxorubicin? Aren't they also insoluble and given IV? Last time I checked, we used them for half a century and saved millions. Oh, now we think differently? I see, Fail Fast: that's how we think now. And mine, whatever it is if it is not a drug, has already failed. Nobody likes to take risks. Soapbox meme for the day: If nobody takes risks, how do we make progress, exactly? So, maybe I am in good company: paclitaxel and doxorubicin would also Fail Fast today.

It's doable. Nobody likes it but it's doable. Sterile-filter the emulsion components and then bring the particle size below 200 nm. Nice. How do I do that? With a microfluidizer. And why nobody likes it? Oh, because the microfluidizer is a dirty machine and where you make Good Manufacturing Practice is called a clean room. Impeccable logic. But a place in California may do it. For a fee, of course. Oh, and you have to buy the machine. Buy what? Or lease it, whatever. People may not like it, but the whole thing works like a charm. Except, of course, when the microfluidizer stops for no reason in the middle of the run. Media fill looks good. Drug is stable for months in the new formulation. Release testing coming together nicely.

I am running out of money. Burned through not just one but two DoD grants and all my research kitty. Nothing saved for the swim back: talk about risk-taking. At least the repeat toxicology is paid for and looks good. The drug, the real thing this time, is safe. They even did ECGs on the dogs. Thank goodness I didn't have to read those, but they are normal: no QTc liability. Can't drop the ball now, but I really need money. Here is how you do it: silence the inner soapbox and enchant the big pharma suits that are coming over. Use the right words. It's not early stage anymore. Asset totally derisked. Sure it's ready for prime time. It works. I am a natural. Maybe I should have done this before. A lot of nodding around the table. The suits must be in awe with the great pharmacokinetics, long half-life, and fabulous safety. A hand goes up. I am sorry? Sales data? Sales of what? What is the unit price? No, no, no, we are not there yet. I haven't even filed an Investigational New Drug (IND) application.

Something different now. Analysts who advise big-time investors. They don't wear suits. Sweaters for sure. Maybe black tees a la Steve Jobs. They like new things and totally live by risks. Sounds like my crowd. And don't forget, they can get tons of money from people who already have tons of money and want to make even more money. My crowd? Voices out of a polyphone. Yes, it is Hsp90. Yeah, the chaperone. Sure, I know, it has been around for a long time. But this is a completely new story: nobody ever tested a cancer drug that goes to a subcellular organelle: that's really where the action is. Yes, Hsp90. And mitochondria, they used to be bacteria two and a half billion years ago, but they turned out to be important in cancer. I know that too, Hsp90 drugs didn't fare well in the clinic. Lot of toxicity, basically no efficacy. Yes, very unfortunate. But this one has a completely different mechan…Sure, I would like to hear that perspective. I am sorry, did you say, Wall Street doesn't believe in this target?

Triaged the first time but funded on the resubmission. Could have been worse. This one is a grant from the National Cancer Institute. And a nice award from the Gateway Foundation is coming too. Enough to pay for the clinical trial. Single site, standard phase I. Accelerated dose escalation. Up to 35 patients with advanced cancer. All comers. Drug vials ready to go. And a fantastic clinical investigator to run the trial. You really don't want me in the clinic. The only thing missing is IND approval. Right, there is that. No, not a commercial IND, investigator-initiated IND, thank you very much. The FDA people are the nicest in the world. Super-helpful, don't believe otherwise. Or maybe they just feel sorry for the clueless applicant. Thirty days to respond to the questions. Totally getting a promotion to a higher rank of telephone operator. And publisher of FDA modules. And certifier of United States Pharmacopeia (USP) . recommendations. And fixer of Chemistry, Manufacturing, and Controls deficiencies. Oh, and let's not forget the specs for polytetrafluoroethylene filters. Then the examiner mutters two words at the end of a phone call. Good luck. Then, nothing. No more questions, e-mails, or phone calls. Right on the thirty-day mark. Were you expecting this? It's a letter; it says study may proceed.

What would the day look like? The first patient to be dosed. Maybe I should go to the clinic: it's in town, not far from where I am. I don't think I can pass muster as one of those confidence-inspiring docs in pharma ads. But I do well as chief executive officer. The cufflinks look good, and so do the shoes. I can impress the family. My Italian accent can pass as straight from South Philly, so I have that also going for me. And I can more than hold my own if I need to talk about Philadelphia Eagles football and worries with Jalen Hurts' arm for next season. I used to be good with my patients. Or at least I convinced myself of that. Yes, this is an experimental drug straight out of our backyard, right here in Philadelphia. No, I don't know if it will work, but I sure hope it will. And thank you, thank you so much for being part of the trial. What if I make these people even sicker than they are? I took an oath a long time ago. Anyway, I know the literature on phase I studies, chances are it just won't do anything, so nobody gets hurt and I am finally done with it. I never thought this moment would arrive.

There is none of that. January 10, 2022. It's just a late-night e-mail on the anniversary of my mom passing from lung cancer. Hey, the first patient did great at the starting dose of Gamitrinib. No problem whatsoever. The next patient will now get twice the dose. I hope we get that started this month. Happy new year. And that was that. Twelve years, 10 months, and nine days from that Journal of Clinical Investigation paper.1

Affiliation: 1The Wistar Institute, Philadelphia, PA

Dr. Lidia Schapira: Welcome to JCO's Cancer Stories: The Art of Oncology. I'm Lidia Schapira, Associate Editor for Art of Oncology, and Professor of Medicine at Stanford University. And I'll be the host of this show.

Cancer Stories is brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care.

You can find all of the shows including this one at podcast.asco.org. With me today is Dr. Dario Altieri, president, and CEO at the Wister Institute. We'll be discussing his Art of Oncology article: Wall Street Doesn't Believe in This Target. Our guest is a named inventor for patent number 2,699,794. Titled: Mitochondria Targeted Anti-Tumor Agents. Dario, welcome to our podcast.

Dr. Dario Altieri: Thank you so much for having me, Lidia. It's a great privilege.

Dr. Lidia Schapira: My first question to you and to our authors is this, people who enjoy writing are usually also readers, what are you reading now?

Dr. Dario Altieri: Well, absolutely it has been a passion of mine since the floods. I am an absolute avid reader of novels, and history, in particular, contemporary history and modern history. Those are my favorite topics.

Dr. Lidia Schapira: Do you read in English, Italian, or other languages?

Dr. Dario Altieri: I typically read in English, even though some of the Italian literature is best read in the native tongue. And so, I am still attached to that.

Dr. Lidia Schapira: You're clearly a very accomplished scientist. But tell me a little bit about your writing in this particular area in what I'll call creative nonfiction. How has this writing helped you perhaps process experiences or communicate with others?

Dr. Dario Atieri: It has been, it's been a passion of mine for a very long time, I think. In finishing up college, of course, my major was contemporary literature and philosophy. The question was whether to continue on in a classic literature career or go to medical school, probably the wrong choice was made. But it has remained with me for a very long time, and it's a form of expression that I truly enjoy.

In writing, this particular contribution was a bit transformative for me. It doesn't happen every time that you write a scientific article to express a little bit about yourself and your passions and dreams.

Dr. Lidia Schapira: Let's talk a little bit about your passions and dreams in this article. You described an intensely personal journey of 12 years that led to the discovery or the availability of this drug now in the clinic. When did you think that you wanted to share this story with your colleagues? And tell me a little bit about the process of writing this article?

Dr. Dario Altieri: It has certainly been a roller coaster experience. I would like to describe it as life-defining and life-changing. I've learned so much and so many things, not just about the process, but also a little bit about myself.

I recognize reaching the clinic, especially in a phase one trial, is really just the beginning. But for me, as a basic scientist, somebody who has seen his last patient in the 13th century. As a basic scientist, that was a little bit of a milestone, and I wanted to share what it took, the experiences that I lived through, especially with our youngest colleagues, scientists, and doctors, starting their own careers in oncology, whether it's basic research, clinical research, translational research, I really don't think it matters. And so, issues of resilience, staying the course, passion, and not really giving up are the parameters that I had hoped to convey with this contribution.

Dr. Lidia Schapira: In your article, I was so impressed by how you used humor, often self-deprecating humor, and the particular narrative style and writing style that you chose and defended as you were revising it.

You know, this choppy phrasing, a staccato, and you said, this is what it feels like, how can I pack it into a small number of words and describe it all? Tell us a little bit about how you allowed your imagination to take over and how you found the proper voice and style for this particular narrative.

Dr. Dario Altieri: Again, it's been a thrilling experience and it's been a thrilling experience to answer to the editors and the reviewers of the JCO, who provided incredible insightful comments.

The challenge was, how do I tell a story without sounding obvious, fright, or expected, and more importantly, without sounding boring? And I think to paraphrase one of our reviewers about this journey. What the reviewer said, the author, that would be me, has encountered many of the absurdities of the path in drug development, something that we don't talk about too much because it's been the realm of a drug company for the longest time.

And so, I wanted to try to capture that absurdity in a positive way. Things that the reviewer indicated, may be second nature to the pharmaceutical industry, but for academic investigators, that's been publicly funded for 30 years, is not second nature and is unusual, and is a world all in itself.

And so, that was the impetus of trying to use literature advice on short sentences that are really intended to convey the impression of the moment that was what I tried to accomplish.

Dr. Lidia Schapira: Well, you certainly picked a catchy title, and we have not published this sort of article in Art of Oncology before. For our listeners, tell us a little bit about why Wall Street doesn't care about your discovery?

Dr. Dario Altieri: Unfortunately, I think, I mean, I don't know for sure. But I think that dealing with this particular molecule, heat shock protein 90 in the clinic has been difficult.

Hsp90 has long been recognized as an important cancer target. There have been several generations of small molecule inhibitors that have been tested in the clinic. And unfortunately, I hope I'm not offending anybody, but unfortunately, the clinical results of those studies, and some of them moved all the way to really large phase two trials have been disappointing.

And so, that is the idea that perhaps this was a dead target. And therefore, trying to leverage industry or biotechnology interest around it was quite a remarkable challenge.

Dr. Lidia Schapira: What message do you want the young investigators to take away from your story in terms of the collaboration between academia where thoughts start, as you say, in your article, and all of the rest of the partners that you actually need it to bring this discovery and this idea to fruition?

Dr. Dario Altieri: Lydia, this may sound trite, I really hope to convey one simple notion. It's not even a message, it's a very personal account. And that is don't give up. If you have run the controls. If you have done your experiments enough time. If you're convinced of the results, if you explore alternative explanations, and you keep coming back to the same conclusions, go for it.

That has been a little bit of my own personal experience and if there are things that you don't know about, that's perfectly fine. Actually, that is the fun of the process, and the things that I didn't know about drug development, I can fill in the encyclopedia. I've learned some of them through people who have been doing this for a living, for a very long time. And that has been truly inspiring for me, a life lesson and professional lesson about how we can think of a drug target that has been discounted and remain true to the core value of strong basic research and try to advance that to the clinic, whether this will ever become something useful for our patients? I don't have the faintest idea. I certainly hope so. But that would be the experiment that is being done right now in the clinic.

Dr. Lidia Schapira: In your article towards the end, you just give us two little glimpses into something that is personal and meaningful to you by telling us that there's an anniversary of a loss, the passing of your mother from cancer. Can you tell us a little bit more about that, and why you chose to put that sentence just where you did?

Dr. Dario Altieri: I didn't know if anybody would have noticed, frankly, so I appreciate you bringing it up, Lidia. It's been a very personal journey for me as well. Both my parents died of lung cancer. They were a different generation. Both were heavy smokers.

I remember those dates very well and I remember the void that they're passing is created. And so, I thought it was an interesting circumstance, that in fact, the first patient was enrolled in a clinical trial, the notion about that and of course, I am technically conflicted.

So, I am not supposed to know anything about what is happening in the clinic. But it was interesting that the first notion about the first dosing came on that day, on January 10.

Dr. Lidia Schapira: Well, I'm sure other readers will notice that too, the timing of that in the article and the fact that there was some emotion implied, I think, in how you chose to end your story by saying that this had happened in the clinic, but somehow, you were not there, that you had to be removed.

Tell us a little bit more about that, about why you needed to be removed from the clinical site and why do you talk about yourself as a former doctor? In my mind, once you are you always are, but somehow you feel that you need to make the distinction. What does it all mean to you?

Dr. Dario Altieri: Well, Lidia, let me just say you don't want me in the clinic right now. At 64years of age, like I said that the last patient was a very long time ago. I have to say, sometimes I miss those days, just as a personal account. I need to be removed because I'm technically conflicted on the trial, I was the IND holder, and then the FDA asked me to transfer the IND to the clinical investigator as proper because I'm not involved in patient care or research, in this particular case.

And technically, because I am the inventor on a patent, I could potentially stand to benefit financially from the results of the trial, something that is certainly not on my mind, but that I have been reminded of.

And so, I try to stay away as much as I can. Obviously, I think about this every day. But whatever information I can gain, that I can gather from my colleagues across town will be wonderful, but I'm not the one initiating those calls.

Dr. Lidia Schapira: So back to the humorous side of your essay, you say that you've learned to be a telephone operator and a mailman, and a whole bunch of other things. Have those lessons been useful to the other aspects of your life? Or do you see that as a total waste of your time?

Dr. Dario Altieri: Not at all. Not at all. I have been an incredible component and I think I was trying to be humorous and to take myself seriously, but not too seriously. But in fact, maintaining that level of interaction, particularly with aspects of the work that I've never encountered, for instance, regulatory aspects of an early-stage clinical trial with the Food and Drug Administration, that has been part of the life journey and I only have very good things to say about my experience.

You know, it's been interesting, Lidia, being part of the experience of being a telephone operator and a mailman. I had this sense, and I could be completely wrong, but I had this sense that people out there want to see us taking small risks. They want to see testing new drugs, they want to see new targets being somehow examined, developed, if at all possible.

I had the sense that there was support, you know, for the idea, and this was an entirely publicly funded program. I funded both the preclinical and now the clinical trial of Gamitrinib out of the American taxpayer's commitment and in many different study sections, in dealing with the FDA, in dealing with other regulatory consultants, I always get the sense people who wanted to help, then had perhaps the mindset, okay, we don't know whether this is going to work or not but let's give it a try. Let's give it a shot. It was wonderful, that was an absolutely awe-inspiring experience.

Dr. Lidia Schapira: I'm glad they did and I'm glad you shared your experience with all of us. Is there something else that you'd like our listeners or your readers to know about you or this story?

Dr. Dario Altieri: I just would like to say that I would do it again, 12 years, I would do every step of the way but I think I'm done. If I were to start over, I'll do it again, but I don't think I'm ready to do it again with another target.

Dr. Lidia Schapira: And with that, I want to thank you and I want to thank our listeners. Until next time, thank you for listening to this JCO's Cancer Stories: The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple podcasts or wherever you listen.

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