Small Molecules, Big Impact: An Interview with Dr. Cheryl London
Explore the history and impact of small molecules in this fascinating discussion. FidoCure’s Chief Medical Officer, Dr. Gerry Post interviews Dr. Cheryl London about their application in canine cancer treatment.
Dr. Cheryl London is a world-renowned expert in veterinary oncology and targeted cancer therapies at Tufts University. Her pioneering work began in 2000 when she collaborated with SUGEN to develop Palladia, one of the first targeted small molecule drugs approved for veterinary use, treating canine mast cell tumors driven by KIT mutations.
Since then, Dr. London has worked on over 10 different small molecule inhibitors, some facilitating translation to human oncology while others focused on new veterinary therapies. Her expertise makes her arguably the most experienced researcher in this cross-sectional field of human and veterinary medicine.
Dr. London works closely with FidoCure, a company dedicated to bringing innovative targeted therapies to veterinary patients. As their Chief Medical Officer notes, Dr. London is a "true leader and visionary" whose insights are invaluable to their mission of expanding access to small molecule treatments.
She is passionate about making these therapies available beyond just specialty practices, aligning with FidoCure's goal of improving accessibility through primary vets. With her unparalleled expertise, Dr. London envisions small molecules increasingly integrated into standard protocols for pet cancers, mirroring the paradigm shift they drove in human oncology.
We invite you to join in this exciting conversation.
Transcript:
Dr. Gerry Post:
Today we're here discussing the use of small molecules, targeted therapy, in veterinary medicine. I am Dr. Gerry Post, the Chief Medical Officer of FidoCure, and I'm here with Dr. Cheryl London, a longtime friend, colleague, and importantly for this discussion, a true leader and visionary in the field of targeted therapies used in veterinary oncology. Dr. London is the Associate Dean for Research and Graduate Education, the Engen and Dusty Professor in Comparative Oncology and a research professor in immunology at the Cummings School of Veterinary Medicine at Tufts University. Thank you so much, Cheryl, for joining us today.
Dr. Cheryl London:
Thank you for having me.
Dr. Gerry Post:
Our pleasure. My pleasure. And so what we really wanted to talk about today was targeted therapies. And let's start from the beginning. How and why did you start to take an interest in small molecule therapy in veterinary oncology?
Dr. Cheryl London:
Many, many years ago when I was in graduate school, I was studying mast cell cancer in dogs and identified the presence of a mutation in a gene called KIT. And following graduate school when I took my first position in veterinary academia at UC Davis School of Veterinary Medicine, I began working with a small company called SUGEN that was developing small molecule inhibitors for specific proteins that were known to drive cancer. And so we were fortunate enough to begin collaborating with them on the small molecule inhibitor toceranib, now called Palladia, which was approved by the FDA for use in veterinary medicine in 2009. This drug was also an inhibitor of KIT. And because we knew there was mutated KIT in canine mast cell tumors and partnered to develop this small molecule inhibitor of KIT to treat canine mast cell tumors. And it worked well and is now part of the care for dogs with mast cell tumors.
Dr. Gerry Post:
And I was at that meeting at SUGEN and it was so many years ago, but just for those people who are not of our generation, when was that?
Dr. Cheryl London:
We initially started working with them in 2000 and it was on the heels of the development of a drug called imatinib, also known as Gleevec, which was created to treat chronic myelogenous leukemia by targeting a fusion protein called BCR-ABL that occurs in about 90% of human patients with chronic myelogenous leukemia (CML). And it really was a blockbuster small molecule inhibitor and opened the doors for this class of agents in the context of cancer treatment.
Dr. Gerry Post:
Fantastic. And if you can remember, how many small molecule therapeutics have you been involved with, either with the development phase or the testing phase?
Dr. Cheryl London:
Probably at this point, I've been involved in the evaluation of over 10 small molecule inhibitors in veterinary medicine. Some of those projects have been specifically to facilitate human translation and others have been with the hope that we could eventually leverage the data we've generated in our patients to develop similar small molecule inhibitors or targeted therapeutics for our patients. Just to name a few, we worked with a drug called Verdinexor, also known as KPT-335, which has a human counterpart called Selinexor, which is KPT-330. And the studies that we did in dogs with Verdinexor helped facilitate the approval of Selinexor in human oncology. We subsequently obtained conditional licensure for Verdinexor for the treatment of canine lymphoma. We worked with a couple of other small molecule inhibitors. One was a heat shock protein 90 inhibitor, another one was a small molecule inhibitor of a target called PI3 kinase delta. And all of those projects helped facilitate human drug development. We've also worked with other targeted therapies like antibodies as well in the context of canine cancers.
Dr. Gerry Post:
Given your incredible breadth and depth of experience, not only with academic research but also with bringing two of these molecules to veterinary medicine, I would dare say that very few people, if anybody, has as much experience with small molecule therapeutics in veterinary oncology.
Dr. Cheryl London:
That may be the case. It's largely because I'm so much older than everybody else because I started much earlier.
Dr. Gerry Post:
You did.
Dr. Cheryl London:
I've been doing it since the year 2000, so that's a long time.
Dr. Gerry Post:
It is. And so certainly I, personally, and we here at FidoCure appreciate your expertise incredibly. One of the words that you used when we spoke just the other day is in this next question. Why do you feel that small molecules are relatively easy to use? And that was a word that you used and I was just so tickled and thrilled that you used that word easy. Can you explain why you feel that way?
Dr. Cheryl London:
Small molecule inhibitors for the most part are drugs that are given by oral administration. On the human side there are over 80 FDA approved small molecule inhibitors now, most of which are for the treatment of cancer, although some are for other kinds of diseases, and the overwhelming majority of them are orally given. And that's partly because in order for them to work, there has to be some sort of continuous administration or intermittent, every other day, administration for them to be efficient enough to inhibit the target they're trying to inhibit.
Because they tend to have relatively short half lives, meaning that they're working by inhibiting a protein and then eventually that inhibition goes away, most of the time they only work for 12 or 24 hours and then they stop working because they're out of the system. And unlike other anti-cancer agents, when we think about chemotherapy agents, for example, which are DNA damaging agents, which have to be given, for the most part, intravenously, (although there are some oral ones) and damage DNA and have a long-lasting effect, the small molecule inhibitors are relatively easy with respect to addressing side effects because those drugs leave the system.
When you give a chemotherapy agent by intravenous injection, you've given it, you can't take it away. The side effects are going to happen. They may happen for days and days and days, and you can't do anything to prevent those side effects. If you've perhaps given too much of a drug or the patient happens to get sick, you have to wait out potentially a week of toxicities. In the small molecule field most of the time you can stop the drug and 24 to 48 hours later after the washout, their side effect has resolved. Not always, but most of the time.
It's much easier to tinker with dose and regimen on a weekly basis. This patient's having some diarrhea, let's just lower the dose and see how they do, or let's give it every other day instead of daily and see how they do. And so it's more of an art to get to that dose that's tolerable and still effective without having to go through these extended periods of waiting for a side effect to resolve or waiting for the white blood cell count to come back up. They're also far less likely to be associated with fatal toxicities, which is really important, whereas you can get fatal toxicities with injectable chemotherapy agents.
Dr. Gerry Post:
And I remember years ago you and I spoke about one of the other ways to handle minor toxicities with targeted oral therapeutics, and that's a term you coined, I believe, drug holiday, which it's just incredibly descriptive. People understand that. And I can't tell you, when I was still in clinics, how many patients and clients that it worked for, giving them a drug holiday, allowing the toxicities to abate and then starting them on either a lower dose or a different dose. Those different mechanisms were incredibly easy for us to do in the clinic. Because of the relative ease, the next question that I have for you is, really, should oncologists and GPs feel comfortable using this class of drugs? And if you feel so, why?
Dr. Cheryl London:
I think most of us should feel comfortable using this class of drugs for a couple of reasons. One, invariably, even if the drugs haven't been approved for use in veterinary medicine, there is a lot of data associated with their use through activities needed for them to be approved on the human side. Typically, some studies were done in laboratory research dogs that gave dose and regimen and give you an idea of side effects and what to expect. But more than that is that there are decades of use behind these small molecule inhibitors on the human side, and they are now intricately woven into therapeutic combinations that are used routinely across a wide array of human cancers. They are routinely administered to human patients. They have been routinely administered to human patients for decades, and they represent part of standard of care for human patients.
And so we have so much data that tells us that these are safe and effective on the human side, that there's no reason to expect that we shouldn't be able to find a dose and regimen that's safe and effective for our patients. Now, there will be exceptions to the rule. There are some drugs that probably we won't be able to use, some drugs that'll have really unique toxicities in dogs. But in large part, for most of them, when we've moved them over back from the human side, we've been able to find a dose and regimen that's effective. And it's going to take a little bit of time to do that, but I think we, particularly in the oncology community, have started to do that mainly because we are currently very limited by our ability to use dose intense multi-agent chemotherapy protocols.
When you think about how chemotherapy is given to people, they typically give multiple chemotherapy agents at the same time on the same day by injection together. And people have side effects from those, but they're generally tolerable. Our patients don't tolerate multiple drugs given on the same day. They have trouble sometimes just with one drug, one chemotherapy drug given by injection on a day. And so one of the nice things about the small molecule inhibitors is that you can sometimes combine them together very effectively. We've done two and three drug combinations and had really low levels of side effects, they're easy to adjust. But more importantly, because we can't give chemotherapy agents the way the human side gives them, we are very limited in how we treat our patients. We've had the same five to six drugs, maybe seven drugs that we've used for the past 30 years, and we have not changed outcomes for our patients. And so it's really a good time to be leveraging all that experience from the human side where they've changed outcomes for their patients by incorporating these small molecule inhibitors.
Dr. Gerry Post:
Relatedly, you and I had a short conversation about a foundation that really is focusing on equivalent problem in people, but also addressing the access to care crisis that we're facing in veterinary medicine. I'm wondering if you can tell the audience what this foundation is and what they're trying to address and why you think it's so important.
Dr. Cheryl London:
The Stanton Foundation is focused on what's called the spectrum of care in veterinary medicine, which is expanding the types of things that can be done in the general practice setting to address the needs of veterinary patients. There are a large number of veterinary experts out there who are in practice and they're incredibly good at what they do, surgeons, oncologists, internists, dermatologists. But the reality is that there are not enough of them to address patient needs and so it makes it very difficult for the community of veterinary medicine to effectively provide care for owners of animals who either can't get into a specialist because there's a two-month wait, or can't get to a specialist because of geography, or can't get to a specialist because they can't get the time off of work. And the human side is facing the same health crisis, which is that there are plenty of populations that can't get access to healthcare and it affects your outcome if you can't get access.
I think both the human and veterinary medical fields need to address this inequity and realize that we need to provide a spectrum of care to our patients and that some of that is going to have to be administered in the general practice setting where those people who can't get access have a relationship already with their primary care veterinarian. And while all of us would like to see every cancer patient seen by a veterinary medical oncologist, I just don't think it's feasible given our numbers and where we are at right now in terms of capacity. It makes sense to try to provide some level of care that doesn't hurt the patient and may help them at the level of the general practitioner. And small molecule inhibitors are a nice way to go. It's one in which the practitioner can assist with helping with the dose and helping manage blood work and physical exams. There isn't anything complicated with the use of small molecule inhibitors like there is with injectable chemotherapeutics that require specific handling. I think it represents a unique opportunity to provide a spectrum of care to cancer patients in veterinary medicine in a way that we haven't before.
Dr. Gerry Post:
I just love that term, spectrum of care, and that's access to care. Spectrum of care is something that I know I know FidoCure is incredibly committed to. Last question, I want to be cognizant of your time, really. Given your experience and expertise with these drugs, how do you think that they will impact veterinary medicine now and in the future?
Dr. Cheryl London:
I'm really hoping that as a community, both specialists and general practitioners will begin to use them and become more comfortable with them. I think using just Palladia as an example, that's a drug that can cause significant side effects. We learned how to manage it, we know how to dose it now. I think practitioners should feel comfortable using that drug. And I think initially it was viewed that it would be something that only oncologists could manage administering, but most of us feel very comfortable working with practitioners to help them with dosing and managing toxicity. But more than that is that I think as with human cancer treatment, I expect that veterinary oncology will eventually adopt inclusion of a spectrum of small molecule inhibitors into our standards of care over time. Because, in reality, if we don't, then we're losing an opportunity to really advance care for our patients the way they have on the human side.
Dr. Gerry Post:
Fantastic. Always a pleasure to talk with you, Cheryl. Thank you so much for your years, dare I say, decades of commitment to the field. And thank you.
Dr. Cheryl London:
Thank you.
