Dr. Guannan Wang (00:02)
Hello everybody. ⁓ Welcome to the second episode of the VetOmics podcast, Genomic diagnostics and the precision medicine in veterinary oncology. This is Dr. Guanan Wang. I'm a genomic scientist and the founder of VetOmics. Our company is dedicated to delivering the best in class, high clinical actionable genomic tests.

for pets with cancer. As we all know, precision medicine has transformed the human oncology by enabling treatments, prognostication, and diagnosis tailored to each patient's unique genomic profiles. In veterinary medicine, we are making strides, but challenges remain. For example, we don't yet

have the comprehensive genomic understandings in pet cancer and access to effective genomic guided therapies is often limited. At Vetomics, our mission is to help close these gaps by generating better data, advancing education, and fostering conversation with key stakeholders about the practicalities

challenges and promises of applying genomic diagnostics and precision oncology for our furry family.

I'm absolutely thrilled to be joined today by Dr. Barbara Kitchell a dual board certified specialist in internal medicine and oncology. Dr. Kitchell truly is a ⁓ leader in veterinary medicine as a clinician, a scientist, an educator, and a mentor to so many of us. She has been at the forefront of

driving the expansion of veterinary pharmacopeia and always striving to ground new therapies in sound signs. Her depth of knowledge and attention to details are truly remarkable. And despite all her accomplishments, she remains one of the most curious and eager learners that I know.

Her impact is not only through her own clinical and research work, but also through the countless students, residents, and colleagues she's mentored throughout her career. And I'm honored to be one of them. Dr. Kitchell's career spans decades of leadership. She received her DVM from Purdue.

Barb (02:57)
Hello.

Dr. Guannan Wang (03:07)
completed a residency and a PhD at UC Davis. She went on to teach and lead oncology programs at the University of Illinois and Michigan State. She is currently the Director of Residency and Specialty Intern Training at VCA hospitals. And she is also a past president of the Veterinary Cancer Society and has authored more than

a hundred scientific papers and book chapters. With all that titles and accomplishments, I'll be honest. At first, Dr. Kitchell felt almost unattainable and so intimidating, but I'll never forget a moment at VCS two years ago. So I was asking a question during a session and Dr. Kitchell was sitting

not too far away from me. And afterwards, she actually came up to me and said, that's exactly what I wanted to know too. That moment really shifted my perspective ⁓ about her, right? Since then, she's been an incredible collaborator and a mentor on this journey. Dr. Kitchell, thank you so much for being here.

Barb (04:16)
You

Dr. Guannan Wang (04:35)
And we are honored. So do you want to say a few words before we begin or shall we jump right into the questions that I'm eager to ask you?

Barb (04:38)
Stop.

Well,

I will say I have been doing this for decades and because of Molecularly targeted therapeutics now I can't retire I was hoping But no there's too much work to be done there's too much to learn and I'm very very honored and excited to be partnering with you in vet omics

Dr. Guannan Wang (05:05)
Mm hmm. Yeah.

Barb (05:13)
to really expand that personalized medicine space for care for our animal companions. It's just phenomenal what the future holds for us and the direction that the profession is going. So I appreciate you for being a pioneer in this space, for helping us to move animal care forward. So yay. So this is gonna be a fun conversation, I hope.

Dr. Guannan Wang (05:35)
Yay.

I hope so too. And the feeling is mutual. Yeah. All right. So let's jump into the questions that I want to ask you as a clinician. So how do you make decisions in recommending genomic testing? First, I want to begin with how many new patients do you see weekly on average?

Barb (06:04)
Well, ⁓ it varies, of course. It fluctuates. And ⁓ we're coming up on some interesting economic times, which may impact all of us in how many patients we see. Typically, I see two to four new patients a day on my receiving case. So. ⁓

Dr. Guannan Wang (06:07)
Mm-hmm.

I know. Yeah. Yeah.

Barb (06:25)
It really does vary with time of year and ⁓ owner's interest in pursuing advanced care for their animals. ⁓

Dr. Guannan Wang (06:29)
and

Absolutely.

Okay, absolutely. Two to four, a day. That's quite a lot. Yeah, that's a lot. And do you recommend genomic testing for all of them? If not, what percentage would you say?

Barb (06:40)
That's Yeah.

You know,

what has happened with me over the course of this field expanding is I initially started with the relapse cases, the cases for whom we had no more standard of care options, ⁓ the disease processes that had no standard of care, right? The really weird tumors.

⁓ And now that I think all of us are becoming more comfortable with the information that these tests provide to us, it's like, okay, move it farther forward, move it farther forward to the extent that...

You know, in human medicine, if you have breast cancer, lung cancer, you you name it, you will have a molecular profile. It's just what is accepted as the best evidence-based medicine that you can acquire. And so for me, I have found myself more recently saying, I'm gonna do this up front. If I have a client or an owner who is

interested in pursuing optimal care for their animal, I'm going to recommend this upfront. And that's what I've kind of transitioned to doing now.

Dr. Guannan Wang (08:14)
we kind of see the same shift and the same spectral. For our frequent users, so we see cases that are more recent, newly diagnosed, and the doctors and the owners are pursuing genomic testing to guide treatment as a front line or early options. But we also have those

users that don't use genomic testing a lot, but they do send us their most challenging and the last resort cases. So from based on from your experience, you kind of shift from that latter category to the more frequent, right? So and that also ⁓ kind of is consistent with the trend in human medicine now, because ⁓

Barb (08:59)
Yeah.

Yeah.

Dr. Guannan Wang (09:12)
20 years ago when precision medicine was first emerged, And a lot of these ⁓ targeted therapies, genomic guided therapies, they were approved as a third line, fourth line, Therapies after you pretty much exhaust all the other options, standard of care options. But there is a big shift that a lot of these genomic guided therapies, whether it's

target therapy or immunotherapies or other newer class of drugs, they are actually approved as front line and in pan cancer settings. Yeah, so that's exactly the progress that we are also experiencing right now. ⁓

Barb (09:50)
frontline.

Mm-hmm, mm-hmm. Yeah,

absolutely true. ⁓ you know, it's clear that putting molecularly targeted therapeutics frontline, it can prolong lives with much less toxic ⁓ outcomes for patient. And so we're hoping as we gain experience in this space, we'll be able to offer the same to veterinary patients. I mean, it's early days for us. We have so much to learn.

But following the trend of human oncology, this is what we need to be doing.

Dr. Guannan Wang (10:28)
Absolutely.

Yeah, I agree. Yeah. So another question I have is that what factors influence your decision to recommend genomic testing? how do you recommend it for certain cancers? Or do you recommend it for a certain stage? How do you think some cases are prioritized?

Barb (11:06)
Well, you know, I had been thinking up until recently that ⁓

Dr. Guannan Wang (11:06)
over others.

Barb (11:13)
The disease processes for which we have robust standard of care options and for which we have really good ⁓ prognostic features and that we believe we understand the disease process like lymphoma, for example. So I have tended not to profile lymphomas because I have tended to say, well, I know I can get this much time on average and this is the course

of care that we would anticipate giving us the best outcome. But I realize that thinking is really flawed because there are subsets of patients within that broad category. So, know, B-cell lymphoma in human medicine has 36 individual subtypes.

And we, in veterinary medicine, we like, well, there's B, there's T, there's T-zone. We don't have anywhere near the depth of understanding that we should have. So going forward, I think we need to really reconsider who gets profiled. And ⁓

how we bring that conversation up with clients early in the interaction that we have with them, even first consult clients. This is where the science is. And if you would like to ⁓ be involved and approve us moving forward with this type of testing, I think, number one, it helps us learn about animal cancers in general. But number two, it can help your pet

to have the best possible prolonged life with good quality. That's all of our goal, prolonged life with good quality. And I think adding personalized medicine to that is really one of the best things we can do to achieve that goal.

Dr. Guannan Wang (13:03)
ruling.

Absolutely. So from our end, you mentioned that for cancers with a good standard of care that you tend not to profile previously, right? So we actually noticed that ⁓ some doctors, they tend to send us a certain type of cancer, for example lymphoma.

And other doctors, tend to send us lung adenocarcinoma or others that they tend to send us hemangiosarcoma ⁓ melanoma. I think they see the benefit of this type of cancer being ⁓ profiled and getting the personalized ⁓ genomic guided treatment to benefit their patients.

But from our metadata, we actually see that well represented cancer throughout ⁓ many, many common and sometimes rare cancers. Like right now, we are approaching 200 cases and we have like 70 different cancer types.

doctors have their ⁓ preferences, but we actually see a pretty well representation of all cancer types getting the genomic profiling and getting personalized treatment, genomic guided treatment. another thing is that we do see cancers like hemangiosarcoma and melanoma ⁓ are being

slightly more ⁓ enriched in this cohort. And we all know why, right? the treatment ⁓ hasn't been, the needles haven't been moved for these types of cancer for quite a long time. You know, we desperately, as a community, desperately are in need of some novel, more effective treatments. So, but overall, I think we see a good representation of all cancers.

Barb (15:11)
Yeah, and just to enhance on that, ⁓ that hemangiosarcoma comment, you know, this new publication that came out in ⁓ Nature in ⁓ scientific reports about real-world evidence couples genomic biomarkers with therapeutic outcomes from the fidocure friends. This is phenomenal.

Dr. Guannan Wang (15:26)
Mm-hmm.

Mm-hmm. Mm-hmm. Mm-hmm.

Barb (15:36)
that adding molecularly targeted therapy to patients who have had surgery for splenic hemangiosarcoma plus chemotherapy and then molecularly targeted therapy totally pushed that Kaplan-Meier survival chart way out. And that's evidence, real world evidence, because these trials are hard to design.

Dr. Guannan Wang (15:50)
Absolutely.

Yeah. Yeah.

Barb (16:00)
because of the individualized mutational profile that you'll get for a given patient's cancer. But this just shows if you can understand the molecular background of the cancer.

Dr. Guannan Wang (16:05)
Mm-hmm.

Barb (16:16)
act upon that, you find actionable mutations, then as a large population you can see that cohort shift and improve in outcome. So it's very exciting times, very exciting.

Dr. Guannan Wang (16:30)
Absolutely,

absolutely. Yeah, yeah. And just to add on that, that's what we have witnessed in so many human cancers, The lymphoma, leukemia, melanoma, non-small cell lung cancer, colorectal cancer. So many cancer types, that are benefit from...

Barb (16:53)
Yes.

Dr. Guannan Wang (16:59)
the genomic profiling targeted treatment. you know, when we talk about non-small cell lung cancer now in humans, it's not just the one type. It's probably 40 types and they each, have different prognostication, indications as well as, targeted treatment options. So that's where we want to see

canine and, other pets as well, right? So eventually we move into that space. Yeah. ⁓

Barb (17:23)
Right. Expanding into feline

has been wonderful. So excited that you're able to do feline profiling. It's something we wanted for so long. That's fabulous.

Dr. Guannan Wang (17:32)
Yeah, yeah.

Well, we are trying to keep it under the wraps, but you just said it. But you know, like with feline, so because the feline genomics, we got it, we got it down. So the genomic test is very, very robust and the results are very, very promising.

⁓ The thing with cats is that the drug metabolism is slightly, yeah, exactly. And with dogs, ⁓ we at least have the Beagle data when they submit to FDA approval, but for cats, we don't have too much drug use data, PKPD whatsoever. So we really want to ⁓ keep it.

Barb (18:05)
Yeah, that's the job.

Yeah.

Dr. Guannan Wang (18:28)
very slow so that we can learn from these proof of concept cases and then we can... No problem. I know. No problem.

Barb (18:31)
Yeah, of course, of course. I'm sorry. I was just so excited about being able to profile cats that... But you're right.

It's gonna fall to us who do more ⁓ investigational therapeutic type work, not those who do. I can't include myself in that anymore. ⁓ But...

to really be able to optimize therapies to that species because it is fraught. There's a lot of dangers in putting new drugs into cats. So, as we've learned over the years. ⁓

Dr. Guannan Wang (18:57)
Yeah.

Absolutely, absolutely. yeah, yeah,

yeah. So we have to kind of do it very ⁓ carefully and ⁓ gathering data while not causing harm, causing the least harm, right? So that's why I was thinking we should only profile like the most challenging case, the last resort cases ⁓ where we can learn from these cases. But yeah, it's very exciting. ⁓

Barb (19:17)
Yes. Right.

Dr. Guannan Wang (19:31)
You know, I, yeah. No, this is super fun. Yeah, I love these conversations. So ⁓ another thing I'm curious is that, so what do you use genomic test for? For treatments or other ⁓ utilities?

Barb (19:34)
I totally derailed your questions, I apologize.

So I have found ⁓ a couple of things that are super helpful. ⁓ Really three large categories, right, which you identify. Number one, are there actionable mutations that we can partner with available therapeutics? And our therapeutic armamentarium is pretty small.

compared to human, where they have over 250 small molecular inhibitors that are available to them. And we have, what, 18, 20? Not very many. But the other space is having something. I just profiled that case that had ⁓ carcinoma of undetermined primary site with carcinoma ptosis.

Dr. Guannan Wang (20:21)
Yeah. Mm-hmm. Mm-hmm. Yeah. Yeah, 20. Not very many. Yeah.

Mm-hmm.

Mm-hmm. Mm-hmm.

Barb (20:42)
And

my hope for the dog was that this represented an ovarian remnant that had ovarian carcinoma, because ovarian carcinomas have a much more favorable prognosis even with standard ⁓ chemotherapeutic approaches. And you were able to come back and tell me, uh-uh, not ovarian, more likely a different carcinoma like pancreatic, which obviously changes prognosis.

understanding what the underlying disease process might be that causes this disease, ⁓ differentiating among really difficult to diagnose cases this anaplastic round cell tumor. Is this a melanoma? Is this a histiocytic tumor? Is this an anaplastic plasma cell? You know, what is this thing that can be very helpful too?

And then finally, also the prognostic features, that the devil is P53 as far as I'm concerned. So if you identify certain P53 aberrations in these cases, then I have a better understanding of how this course might progress for this patient. And it also helps me to maybe position myself better to

Dr. Guannan Wang (21:44)
Mm-hmm. Mm-hmm.

Barb (22:06)
expand my mindset into what can we do to enhance apoptotic cell death in a patient who has an aberrancy in their p53 gene function. So, you know, for me, from ⁓ a investigational mindset, it's like, okay, this is where the work is. This is where we have to work our hardest.

to try to ⁓ save these patients. So for me, that's a very exciting thing. So it's both actionable mutations for immediate therapy. It's understanding the originating cell that caused this cancer when we have trouble diagnosing them.

and it's prognostication, it's risk. What is the risk that this patient will fail early and what can we do to mitigate that risk? So for me, it's all of those things combined is the reason to advance in this space.

Dr. Guannan Wang (23:13)
Love it. Yeah, that's, you know, the main utility off-aid genomic testing, for a cancer patient. I love how you summarize that based on your real life experience. obviously, now we have a comprehensive genomic profile platform where we investigate over 20,000 genes across the entire K9 coding exome.

Barb (23:37)
Yes.

Dr. Guannan Wang (23:41)
we haven't had one case where we fail to identify a actionable drugable mutation. But also in more than 30 % of our cases, we were able to provide some diagnostic clarity or sometimes even diagnostic guidance, for this case. It's exactly like what you said in those,

undifferentiated round cell tumors. those differentials happen to have a pretty unique molecular ⁓ genomic profiles. So if we identify one, that's a good chance. the diagnostic ⁓ utility will only expand as we...

Barb (24:22)
Yes.

Dr. Guannan Wang (24:25)
sequence more as we do more comprehensive genomic filing for more cancers. Because now that we have an unbiased view of many common rare canine cancers where we can really know what mutation ⁓ or what mutation combinations are enriched in certain cancers. And then maybe those become truly pathognomonic for diagnosis.

Barb (24:50)
Yeah.

Dr. Guannan Wang (24:51)
I'm so

Barb (24:51)
Yeah.

Dr. Guannan Wang (24:51)
looking forward to that day. We'll keep accumulating data. Yeah, we'll get there. And the prognostication, as you said, was very tightly tied to the molecular subtypes. So ⁓ right now, in human non-smell cell lung cancer, it's not just one ⁓ disease entity. It's probably 40. So we see a day where

Barb (24:58)
Yeah.

Dr. Guannan Wang (25:18)
maybe hemangiosarcoma has five molecular subtypes and some of them are associated with guarded prognosis. Some of them are actually associated with favored outcome. So that's one concept I think is not very familiar in the veterinary space is that, do you actually have biomarker that can predict a favored outcome? We do, there are many.

biomarkers especially in the heme cancers like leukemia, lymphoma that they actually predict favored outcomes. So we definitely have some hints, hypothesis in hemangio sarcoma. So we'll see how that pan out in the larger study whether we can validate that hypothesis or not. that's,

all the, untouched field So I'm excited to, exploring that. And that will have huge, clinical implications, right?

Barb (26:25)
Yeah, absolutely, absolutely. I mean, hemangiosarcoma is such a heartbreaking disease and we can do better. We will do better as we learn more in advance.

Dr. Guannan Wang (26:27)
Yeah, yeah, yeah.

I know, yeah.

Absolutely.

So now, moving to the the second ⁓ category of my questions is the barriers to genomic testing adoption. So when you do recommend based on your experience, your knowledge, when you do recommend genomic test to a pet owner, so what are the main reasons that they decline?

are like a cost, treatment ⁓ complication, or lack of knowledge, or all of the above.

Barb (27:09)
Yeah.

Yeah, it may be all of the above.

⁓ I practice in New Mexico, as you know, so we have a big ⁓ population of pet owners who are really financially limited. And so ⁓ we find ourselves ⁓ having to compromise our standard of care to accommodate cost ⁓ quite frequently, unfortunately. ⁓ But ⁓ for those clients who ⁓ see the value,

they are willing to expend the cost to have the testing done. I've had a couple of clients that say, it takes so long to get those results back. And in reality, it doesn't. It doesn't.

Dr. Guannan Wang (28:05)
It doesn't, yeah.

Barb (28:07)
You know, we have results within two weeks from the time the specimen, the holdup is getting the specimen out of the diagnostic lab to you, to your lab. ⁓ But then within two weeks, we have information. And then having the opportunity to sit down with the client at that time and go over the findings and outline what opportunities we have for therapy, it's very good. And I also have clients who say,

Dr. Guannan Wang (28:14)
Yeah. Yeah.

Barb (28:37)
Even if this doesn't help my dog, if it will help dogs with cancer, then I want to do it. And that's quite a wonderful feature of pet owners in general. So cost, would say, is a barrier. Lack of understanding, lack of knowledge. But that's our job as clinicians. The original...

Dr. Guannan Wang (28:59)
Mm-hmm.

Barb (29:02)
term for physician is educator, is teacher. So that's what we are here for. We have to help people understand what can be accomplished and what can't be accomplished, right? So yeah, so I would say those are the two biggest things, the cost and the client's level of education, level of understanding.

Dr. Guannan Wang (29:05)
Mm-hmm. Mm-hmm. Mm-hmm. Mm-hmm.

Yeah, absolutely. Yeah.

Okay. And know that, we're here to facilitate that education and to facilitate that conversation. ⁓ Join joining forces with you guys. Yeah, I've learned so much. So this is you just you begin to at first it's a it's a job, right?

Barb (29:35)
Yeah, it's fabulous.

Yeah, it's

Dr. Guannan Wang (29:53)
And then you get deeper into it. You consider it as a career, a ⁓ location, right? And now, it's like after you interact with clinicians like you, hear the stories of the pet and the pet owners, ⁓ it becomes, it's a...

Barb (30:02)
Yeah.

Mm-hmm.

It's a mission.

Dr. Guannan Wang (30:18)
Yeah, it's a mission. Yeah, it's a mission. It's a passion. So I'm sure that's what we are here for. Yeah. Yeah. Yeah. And how do you how how do you think we can improve education and access?

Barb (30:25)
Yeah, absolutely, absolutely.

Well, think opening a conversation to clients, ⁓ with clients, know, here's what the cutting edge is now. This is the most advanced care we can offer. And if you want to avail yourself of this, this is what our recommendations would be. You know, so having that conversation just, you know, off the top of my head, maybe having some more material for clients available to read and to evaluate would be helpful.

Dr. Guannan Wang (30:39)
Mm-hmm. Mm-hmm.

Mm-hmm.

Barb (31:06)
⁓ Yeah, so I think that as it gains more widespread acceptance, then it just ripples out and it becomes more commonplace, I think.

Dr. Guannan Wang (31:20)
Absolutely. And this this happens, you know, in human oncology. ⁓ 20 it first like appeared 20 years ⁓ Beginning of the 2000 and yeah, 2000. Right. And then yeah. And then when when precision medicine really was taking shape was 2010 2011.

Barb (31:32)
Yeah.

Yep.

Right?

Yeah.

Yeah.

Dr. Guannan Wang (31:48)
and it's

been over a decade. And now ⁓ genomic diagnostics ⁓ have become like a routine care, right? ⁓ Part of the routine care. Yeah, so for any, this is a part of the workup when the patient is diagnosed with cancer. I think we are early stage, but as we gain more knowledge, as we have more good data.

Barb (32:00)
care, routine care.

Dr. Guannan Wang (32:17)
as we see more benefit. I think that's really where the crux is. You have this test all of the sudden, not inexpensive, and what can we gain from it? So I think that's really where we need to show both clinicians as well as pet owners the benefit. yeah. Yeah, yeah, yeah.

Barb (32:39)
Yeah, absolutely, absolutely.

Dr. Guannan Wang (32:44)
for the ⁓ next set of questions, decision making in drug prioritization, I think you briefly touched on this ⁓ at the beginning. ⁓ My question would be, how do you prioritize therapies? Do you exhaust ⁓ standard of care therapy before you apply genomic guided therapy? Or is this really ⁓

cancer dependent and patient dependent.

Barb (33:15)
Yeah, I think it's both cancer dependent and patient dependent in the sense that, like I said, we as a community of oncologists have felt comfortable with where the standard of care protocol puts us, then we may say, well, let's hold this until relapse.

Dr. Guannan Wang (33:30)
Mm-hmm.

Barb (33:35)
And at the time of maybe first relapse in a lymphoma, before things have gone so far that there's so little left that you can even offer, maybe that's the time. But as I say, for some of these disease processes, like hemangiosarcoma I think we should profile them upfront, absolutely. I think we should profile the melanomas upfront. Even though we have good immunotherapies that are helpful to us,

curing enough patients. So we need that information to ⁓ move the needle forward. ⁓ The other thing that I've been really interested in is tumor mutational burden, which we really couldn't get at before we had comprehensive genomic profiling, right? Because it's based on number of mutations per megabase. And if you're only profiling a certain number of genes, you can never get to tumor mutational burden.

Dr. Guannan Wang (34:24)
Yeah.

Yep. Yep.

Yep.

Barb (34:35)
But

with this assay, with the VetOmics assay, we can understand tumor mutational burden enough to say, this is a patient that would benefit from immunotherapy, whether it be Gilvet-Mabb or another immunotherapy, because we know that human patients who have high tumor mutational burden tumors are more responsive to immunotherapy across the board, regardless of underlying histology.

So that's an important

Dr. Guannan Wang (35:05)
Exactly. ⁓

Barb (35:07)
thing to understand to guide therapy again.

Dr. Guannan Wang (35:10)
Yeah, yeah, yeah. ⁓ excellent points. You know, I cannot agree enough. people think that genomics is only useful for small molecule inhibitors, or target therapies, like the traditional version, but it's not right. So genomic biomarkers that have been

universally use two stratified patients to predict immunotherapy responders. There is like a tumor mutation burden, microsatellite instability, right? Yeah. the IHC test, like immunotherapy, ⁓ it's wonderful to ⁓ activate your own immune system, right? ⁓

Barb (35:45)
Instability, yeah.

Dr. Guannan Wang (36:01)
target and kill cancer cells. It sounds wonderful. But in reality, know, the response rate is, it varies so much, right? You know, like even with all the biomarker stratification, I think the response rate is around 50%. for ones that respond and works wonders, for the ones that don't, can be, you know, can be actually very, very dangerous and in effect.

Barb (36:07)
What fuck did you do?

Dr. Guannan Wang (36:29)
So, you know, we have ⁓ several research projects going on where we are hoping to identify patients retrospectively from their clinical trial patients, whether we can identify responders or non-responders ⁓ based on genomic profiling like the one based on biomarkers, like tumor mutation burden.

⁓ Not only that, so there is a room for discovery here, right? We know TMB is a well-established immunotherapy biomarker, but there are so many others, and we've seen them in our patients. So, you know, I'm so looking forward. ⁓ But at the first, I'm just marveled about that. Our K9... ⁓

Barb (37:09)
Yeah, yeah.

Dr. Guannan Wang (37:21)
even have all these immunotherapy options. It's just so wonderful, right? Yeah, yeah. Finally, yeah. Kudos to a lot of the colleagues who work in this space where we have these options that we just will help stratify the patients that best respond, be the excellent responder. And also this, you know,

Barb (37:25)
Yeah, finally. Finally. Yeah.

Dr. Guannan Wang (37:50)
It's wonderful that we have them, but they are also not inexpensive. So if we can somehow identify patients upfront so that it's a negative results, it doesn't mean it's bad. Negative results means that we need to look for other options. we need maybe this. Yeah, exactly. We've learned that maybe this patient is not best.

Barb (37:55)
Yeah.

Yeah, we've learned, right?

Dr. Guannan Wang (38:17)
good for immunotherapy, it's a good responder for, for example, imaginib, right, because of the kit PDGFR, amplifications. So definitely, yeah, something that we can all appreciate. Perfect, yeah, yeah.

Barb (38:25)
Yeah.

Yeah. Yeah.

Mm-hmm, yeah, absolutely. And just

to say something totally off the cuff that's crazy, ⁓ employing AI in this space is also allowing a window into repurposed drug therapy, right? That there are drugs that have anti-cancer effect if you have the right molecular profile.

Dr. Guannan Wang (38:40)
Mm-hmm.

Barb (39:00)
that would indicate that this drug could be helpful. And so in the AI space, the sort of the investigational pharmacology people coupled with the bioinformatics people and the AI people like putting all of that information together to find out that there are things that could help your patient even though they're not cancer drugs per se. So that's exciting too.

Dr. Guannan Wang (39:22)
Mm-hmm.

Oh, absolutely.

Yeah, yeah, yeah, absolutely. Yeah, yeah. You and I probably are thinking about the same company or same companies, but super, super exciting. And we definitely need drug access. Especially availability now as you...

Barb (39:39)
Yeah.

Yeah, ⁓

Yeah.

Dr. Guannan Wang (39:49)
As you said earlier, we are selecting ⁓ based on 20 small molecule inhibitors. Most of these are early generation, very old. So not only are they toxicity profile much ⁓ broader than the newer, more targeted versions.

Barb (39:59)
Yeah, and very old, early generation.

Dr. Guannan Wang (40:15)
but their efficacy is also not as good, right? So yeah, so we are, so in that front, so we are actually working with compounding companies where we think, okay, based on the data that we have, we see these ⁓ mutations a lot and these drugs are best to target these mutations. Can we...

Barb (40:18)
That's good.

Dr. Guannan Wang (40:42)
looking to how do we bring these drugs into the veterinary space. We're having that conversation. We actually ⁓ shared our first list just not too long ago. So we hope that we can bring in more drugs. new agents, new generation agents. to ⁓ give you an example, for the entire PI3K signaling pathway, right?

Barb (40:50)
Mm-hmm.

Yeah, new agents, new generation agents would be...

Dr. Guannan Wang (41:10)
There's so many mutations. It's probably the most mutated signaling pathways. And it's involved in so many aspects of the cellular process. And it's widely altered in oncogenesis process. We only have one drug that targets everything that's mutated in this pathway, which is sirelimus reprimisine.

Barb (41:18)
Thank you.

Dr. Guannan Wang (41:39)
Right? So we don't have this, exactly, ages old. Even if we find a perfect PIC3CA activating mutation, we don't have that specific drug to target that mutation. We can only target from the downstream signaling, which is a broader and a dirtier. Right?

Barb (41:40)
Yeah, yeah, you're old.

Dr. Guannan Wang (42:06)
I've heard ⁓ someone say that at ACR ⁓ one year that for precision medicine to work perfectly, you have to have the right ⁓ target, right mutation, the right drug, and the right timing. So everything have to come together, right? So, you know, yeah. So right now we are pretty confident ⁓ with the mutations, with the potential drivers.

Barb (42:23)
Yeah.

Dr. Guannan Wang (42:34)
but there are still other aspects that have to catch up where we can make the whole thing work more seamlessly. But even with that, even with the current paradigm, we've already seen benefits.

Barb (42:52)
yeah, absolutely. ⁓ It's amazing when you get somebody for whom the drug partners well with a mutation, it can be amazing, the response. You know, with targeted therapy for high-grade mast cell, know, surgery alone, four months survival for high-grade, with targeted therapy, I have patients out of four years. I mean, that's just, that's...

Dr. Guannan Wang (43:00)
Mm hmm. Yeah. Yeah. Yeah.

Amazing.

Barb (43:18)
Amazing. That's the miraculous outcomes that we all hope for. That's what keeps us getting out of bed in the morning.

Dr. Guannan Wang (43:19)
Yeah. Yeah. Yeah. Exactly. All of our doctors, they have miracle cases like that. And in a way, that's also ⁓ kind of the reason that we are still here, right? Because this works. At least for some patients for now, but we are hoping to broaden that.

Barb (43:44)
broaden

it, increase the number of patients that benefit. Yep, absolutely. So can I ask my question, which is, how when you're in this sea of 20,000 genes, and now you've identified 3,400 mutations out of this big group of expressed genes,

Dr. Guannan Wang (43:45)
bad and bad benefit increase them. Absolutely. Yeah.

huh, yeah.

Yeah.

Yeah.

Barb (44:09)
How do you identify, how do you prioritize who is the driver in this setting?

Dr. Guannan Wang (44:14)
Mm-hmm.

Yeah. it's a great question. I got asked about that a lot. So especially with our current comprehensive genomic profiling, KNICGP covers the entire coding exome over 20,000 genes. So we typically detect over 5,000.

variants, not even 3,000, 4,000, 5,000 is the minimal. How do we, like these are protein changing variants. They are not even like the silent mutations. So now narrowing that down to a few that are potential drivers of the cancer or the ones that we might be able to target.

Barb (44:46)
my gosh.

Dr. Guannan Wang (45:08)
It's a major task. So just to walk you through the general framework that we use. And it's not unique. So it's common for a lot of genomic companies. So at first, we identify all the genomic differences.

between whether this is a site change, like at one nucleotide, or it's a region change, the copy number of a region. But all the genomic differences between the tumor and the reference genome, right? And this is the variant calling step. And we have established bioinformatics pipelines to do that. And then, we filter out.

Barb (45:50)
Yes.

Dr. Guannan Wang (45:58)
anything that are likely noise or artifact or benign population polymorphism. you know, ⁓ not all dogs or not all people, they share the same genomic.

Barb (46:07)
Mm-hmm.

Dr. Guannan Wang (46:16)
contents not exactly the same, right? So there's always some difference, ⁓ but they are not necessarily disease causing. They just give us all these different features that we each have, which makes us unique, right? So, and we have to filter those out because those are considered ⁓ germline, benign And then, after filtering, so,

Barb (46:18)
Yeah. Yes.

Dr. Guannan Wang (46:40)
We also interpret the variants ⁓ using AI-powered decision tree algorithm. So it connects the biological ⁓ nature of each change, the variant change, to the known functional or clinical impacts.

Barb (47:03)
Yes.

Dr. Guannan Wang (47:03)
In

another word, is this mutation actually causing a protein function change? And if it does, does that have any clinical amplifications? So that's where we need to annotate the variants. And so the annotation is based on a lot of human precision oncology knowledge basis. And also, we also have the K9.

Barb (47:10)
Yes.

Yes.

Dr. Guannan Wang (47:32)
literature knowledge base as well. So we basically ⁓ capture everything that's out there that can explain, that can annotate this variance. Does this have any function? Is this damaging ⁓ variant? Is this associated with any drug response or diagnosis or prognosis? ⁓

human or canine cancers. So we capture that. That's where we annotate that. And after that, now, so the initial 5,000 variants came down to hundreds of somatic, what we call somatic mutations is that they are only present in the tumor. They are not germline. And then,

Barb (48:20)
in the tomb.

Mm-hmm.

Dr. Guannan Wang (48:26)
Now, oftentimes that's where I come in. I'm oftentimes working with hundreds of variants for any given case. And to figure out which variants are likely drivers, so we look at a few key things. One is ⁓ recurrence. Is this mutation seen across cancers in dogs or in humans?

This is where we really leverage a lot of the human databases, human cancer databases, a huge amount of human data. And also we also have growing canine data as well, thanks to a lot of colleagues in this space that we can now finally see that we have some, this mutation has been found and is enriched in this type of cancer. example, PTPN11 is enriched in histocytic sarcoma, which sometimes helps us.

to diagnose the histocytic sarcoma in those challenging rung cell tumors. And ⁓ now, so like with K9-CGP, we are approaching 200 cases and we can already see patterns and enrichment for some mutations in certain cancer types. now eventually we want to, mm-hmm, mm-hmm, yeah, I'm so excited, Yeah.

Barb (49:23)
Yeah.

That's so fabulous!

Dr. Guannan Wang (49:49)
And that's a recurrence, right? We have to see if this happens only once, no literature whatsoever. So it could be important, but not based on current knowledge, right? We can probably deprioritize that. And the second is the functional and oncogenic impact. So is this mutation known to be activating or oncogenic based on experimental evidence?

or computational prediction. Here, that's very useful ⁓ information, for example, a amino acid change from alanine to valine. It could be important. It could, but not always. So that specific amino acid change also makes a difference.

But plus, it's ideal that we actually have experimental evidence to show that these mutations are indeed activating and oncogenic, by mouse studies. But I do want to have ⁓ a plug here that is a known activating or oncogenic mutation ⁓ always the driver for a, even if they are drivers for other type of cancer.

Barb (50:44)
Thank

Mm-hmm.

Yeah.

Dr. Guannan Wang (51:13)
but for your particular cancer, it's always a driver just because of the finding of that mutation. Not necessarily, right? This mutation, give you an example, this melanoma case, you know, have a, like a NF1 ⁓ mutation, right? Very common in canine melanoma. But it's only present in 3%.

of the tumor cells ⁓ in the tumor that has 90 % tumor content, meaning that this tumor is melanoma is oftentimes pretty pure, ⁓ not with a lot of normal tissue mixed in. But it's only 3 % of the tumor allele frequency, ⁓ very low level. What does that mean? It means that

This mutation is only present in the minor, minor subclone of the cancer. And ⁓ it's probably not the main driver or the one that could respond to treatment at that snapshot. And at the same time, we identify a CDK4 copy number gain at 40.

Barb (52:14)
Mm-hmm.

Dr. Guannan Wang (52:37)
amplified copies, right? Yeah, well, we saw that. ⁓ so you tell me, I, do I, just because I found an NF1 mutation that's activating, do I absolutely have to act on it or prioritize that? No, we need to prioritize the one that's more prominent, that more dominant in that particular cancer, right? So this is all very,

Barb (52:40)
Whoa.

Dr. Guannan Wang (53:05)
context dependent, right? You really have to compare that particular mutation across all the mutations that are found in that tumor. That's why I think that comprehensive genomic profiling is crucial in determining which is the real driver, right? Just because you find a, BRAF mutation in the TCC does not necessarily mean that BRAF is the main driver.

Barb (53:08)
Yes.

yeah, super important.

Dr. Guannan Wang (53:32)
does not mean that it will respond to a remorafenib or tramanib in that sense. So we really have to take the unbiased, the comprehensive ⁓ picture. Yeah, that brings me to the third point, is the level of the mutations based on variant allele frequency and based on the level of the copy number gains or the level of copy number losses.

So those are the three ⁓ key parameters that I look at when I try to prioritize which one is the ⁓ potential ⁓ driver for that case. but this is only to prioritize which driver, right? We still have to prioritize which drug is best for this patient, right? So.

Barb (54:02)
Listen.

Yeah!

Dr. Guannan Wang (54:24)
I've not a lot, not a lot of cases, but I've had one leukemia case where we identified EZH2, which is a known driver mutation in human leukemia or lymphoma, right? So, and that's exactly an activating mutation. so happy. But we don't have a EZH2 inhibitor yet

that's available or even compounded for dogs use. So in that case, so we know that EZH2 is probably the driver, but we cannot use the best drug to target it. We have to kind of go down the list to go to alternative options from a lower level evidence.

Barb (54:50)
Yeah.

Dr. Guannan Wang (55:16)
So we oftentimes have alternative options, but it's not as ideal as if we can just target with the best in class drug that are available. yeah, we don't have a lot of those cases, but that's just an example, right, to say that everything have to match. And I'm happy that we are having these conversations.

Barb (55:25)
Yeah, yeah. my gosh.

Dr. Guannan Wang (55:42)
bringing together genomic companies and pharmaceutical companies. And we can kind of ⁓ work together, right? So based on data-driven repurposing or a new drug development. most of the drugs in the human space are developed in the context of genomic guidance.

Barb (55:57)
Yeah.

Dr. Guannan Wang (56:05)
or some biomarker guidance. It can be genomic, can be transcriptomics, it can be proteomics, but under some biomarker guidance. Yeah. Does that answer your question?

Barb (56:15)
Yeah. Yeah. Yeah.

That is so helpful. That is so helpful because it is. It's a big black box. know? Here's this huge number of genes. How you sort through to get to a meaningful answer. That's so helpful to me.

Dr. Guannan Wang (56:22)
Okay. Yeah.

Mm hmm. Yeah.

Absolutely, yep.

yep. Yeah. So, I still have a couple more. I don't know if you still, Chris, I don't know if you still have time, Maybe 10 more minutes.

Barb (56:47)
I don't know if

Sure.

Dr. Guannan Wang (56:53)
Okay, yeah. So, for example, like, how do you manage the toxicity and the side effects side of these newer genomic guided treatments, small molecule inhibitors, the immunotherapies?

Barb (57:07)
Well,

Yeah, I think that's all something that's a steep learning curve for us, right? ⁓ You know, for example, I mean, to me, toserenib is...

Echoladia is a particularly toxic drug when you come down to 50 % of the patients are going to have gastrointestinal side effects at some level or another. So over the course of time and experience, we've learned how to manage drug holidays and concurrent medications, ancillary supportive medications, to make that drug tolerable to our patients.

But as we move into these newer drugs, we're learning more and more. Like the example that we have been talking about is the olaparib plus carboplatin, which is a standard of care combination for BRCA mutated ⁓ human breast cancer, right? Or if not olaparib, the next generation, the next generation.

Dr. Guannan Wang (58:06)
Yeah, Breast cancer, prostate, yeah. Yeah, yeah, yeah, yeah.

Barb (58:14)
And there's some pretty daunting hematologic toxicities. you were very instrumental in bringing together the users who have had first experience, know, first in drug class experience with using that agent and put together everybody's.

⁓ discussion points about here's what I do, here's what I have found, this is what I have seen. So it's not a publication, it's not evidence-based medicine, but as a community of early adopters, I think we can help guide each other.

⁓ through experiential learning of how we use these agents, right? ⁓ In the real world, in our daily practice, this is what I have seen, this is what I have experienced, and this is how I've managed it. So I think for every one of these drugs,

we have to get into that level of ⁓ community cooperative learning. I think that's where we need to go. Yeah.

Dr. Guannan Wang (59:28)
Yeah, absolutely, absolutely. I

agree, 100%. Love that, yeah, we will learn together as a community so much more about the toxicity side effects of many of these newer drugs. think it's effort from everyone, right? So we cannot just dump a new drug and good luck.

Barb (59:51)
Yeah,

and then just move forward. yeah, let's do it daily. ⁓ well wait, daily is too toxic. Let's figure out how to use the drug in a way that's effective. And going back to the human literature, to fully understand in human cases, what do they see? And that doesn't mean we'll see that same thing in dogs. We may see that or we may see something different. But.

Dr. Guannan Wang (59:52)
Yeah, yeah, yeah.

Yeah, exactly. Yeah.

Mm-hmm.

Barb (1:00:19)
to be aware of what this drug could bring. And I'll give you an example of that. I was looking at cardiac effects of tyrosine kinase inhibitors, right? Big problem in humans where prolongation of QT interval in your ECG could indicate that you're going to have cardiac problems from this drug. ⁓

Dr. Guannan Wang (1:00:31)
Mm-hmm. Mm-hmm. Mm-hmm.

Mm-hmm.

Barb (1:00:45)
10 to 15 % of human patients who take Ibrutinib get atrial fibrillation. I didn't know that until I did a dive into the literature. And so now, you know, we're setting up a little study where we do a baseline ECG, and then we put the patient on Ibrutinib, and then we do a follow-up ECG, and we see if we capture any of that. And it may not be true for dogs, but if we don't look, we won't know.

Dr. Guannan Wang (1:00:52)
Mm. Mm. Mm-hmm. Mm-hmm.

Mm-hmm.

Yeah.

Yeah? Yeah.

Absolutely. Yeah.

Barb (1:01:14)
And so those are

the kind of efforts that I think we all have to engage in to really learn how to use the drugs with efficacy but also with safety for the patient.

Dr. Guannan Wang (1:01:27)
Absolutely,

yeah, yeah, yeah. I would even prioritize safety over efficacy because without safety, right, it's hard to talk about efficacy. Yeah, no point. Yeah, and so just to coming back to the olaparib and carboplatum conversation, I think with all the conversation going on, so we now have a pretty solid.

Barb (1:01:38)
Good point.

Dr. Guannan Wang (1:01:54)
I call it safe protocol for, you know, challenge cases, ⁓ new users. So we can start very, very slow and monitor closely along the way before you, increase dose or, putting the drug together more or increase the cycle, right? So I think, you know, we have a very, very safe baseline.

protocol ⁓ now and this is a team effort. I want to take a minute to thank all the doctors that you know came to me and say that okay I had a thought about this or I had a patient about this and it's just amazing to truly team effort. It takes a village to do this. Yeah, yeah.

Barb (1:02:39)
Yeah, yeah. And you

know, we're just standing on the shore of a massive ocean and there's so much we don't know. And so we have to come at this with an open, unbiased understanding and with an open mind and with humility because the science is so massive. We have to really ⁓ work very hard to understand how best to these drugs.

Dr. Guannan Wang (1:02:46)
apps.

Yeah.

huh.

Yeah, yeah, yeah, yeah, yeah,

yeah, yeah, absolutely. Last question ⁓ for you today is ⁓ what changes and advancements would you like to see in this space? What do you expect from us, from yourself, your colleagues? How do we work together to make this more widely acceptable, but also to show benefit?

Barb (1:03:36)
Well, I think the more and more cases that are amassed using this tool, ⁓

Dr. Guannan Wang (1:03:45)
Mm-hmm.

Barb (1:03:45)
better our understanding will be, the better our utilization will be. And I think it's ⁓ incumbent upon us as a community to educate ourselves. You know, we need more of these ⁓ webinars. need podcasts or we need more seminars at the big conferences to help us all learn from each other, I think.

Dr. Guannan Wang (1:04:06)
Mm-hmm.

Mm-hmm.

Barb (1:04:15)
Because that's where we are. We're in absolutely pioneering territory here. ⁓

Dr. Guannan Wang (1:04:16)
Okay. Yeah. Mm-hmm. Mm-hmm. Mm-hmm. ⁓

Barb (1:04:22)
It isn't like we can write this is a phase one clinical trial without the understanding of who would benefit from this trial. ⁓ We're never going to see a signal that this is a beneficial drug. We have to do it more in a real world kind of way to understand it. ⁓ And then, of course, trying to get more drugs.

Dr. Guannan Wang (1:04:41)
Mm-hmm.

Barb (1:04:49)
better drugs and how we bridge that economic, it's a chasm, right? I mean, I had a client who said, I don't want to use metinib generic, I want to use Gleevec. And then they went online and found the price difference, right? Well, the human pharmaceutical space is so incredibly ⁓

Dr. Guannan Wang (1:05:08)
Mm. Mm. Mm-hmm. Mm-hmm. Mm-hmm. ⁓

Barb (1:05:18)
I mean, yeah, for your case with the EZH, whatever you said, EZH2 mutation, yes, you could probably go out and get that agent, but who could afford it? yeah. It's like, how do we move our space forward without having...

Dr. Guannan Wang (1:05:26)
Yes,

Yeah. Mm-hmm. Yeah. Mm-hmm. Yeah.

Barb (1:05:43)
pharmacologic agents that we could use. So that is another area of really heavy lifting that we're going to have to do.

Dr. Guannan Wang (1:05:46)
in

Love everything you said. So this is super fun and truly inspiring, seeing how you work, how you mentor, how you keep us all in shape. So I think the golden years is upon us.

Barb (1:05:58)
Ha ha ha!

You

Dr. Guannan Wang (1:06:23)
So we just need to work super hard and work smart and work as a team to get there. Yeah,

Barb (1:06:24)
We don't.

Yeah, absolutely,

I appreciate your generosity in letting us as a community fumble along, following your expertise and your guidance to try to help our patients the best we can. It's just been a lovely experience working with you, and I really appreciate it.

Dr. Guannan Wang (1:06:40)
Thank

Thank you, thank you. With that, so thank you again for being here and we'll see you soon. Bye.

Barb (1:06:59)
Okay, okay. Thank you so much.