Functional Drug Screening and Genomic Profiling in Advanced Sarcoma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of cancer advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I program and co-director of sarcoma care at Cleveland Clinic. Today, I'm happy to be joined by Dr. Jorge Manrique, head of the sarcoma program at Cleveland Clinic, Florida. He is here today to talk to us about functional drug screening and genomic profiling in advanced sarcoma. Welcome, Jorge.

Jorge Manrique-Succar, MD: Thanks Dr. Shepard. Thank you for having me here.

Dale Shepard, MD, PhD: Absolutely. You're actually joining us from Cleveland Clinic in Florida. Maybe you can tell us a little bit about your role down there.

Jorge Manrique-Succar, MD: Sure. I'm an orthopedic surgeon. I completed two fellowships, one in adult joint reconstruction, and the second one in orthopedic oncology, and I'm currently the program director for the sarcoma program here at the clinic in Florida.

Dale Shepard, MD, PhD: Excellent. We're going to talk today about a feasibility study for drug sensitivity testing, and about genetic profiling. Maybe just to start, give us a little background about drug sensitivity testing and what this study is aiming to look at. What question are we trying to answer here?

Jorge Manrique-Succar, MD: Absolutely. This study is one of the few studies out there, if not the only one, of its kind in sarcoma. We partnership with Florida International University with Dr. Diana Azzam, who has extensive background in drug sensitivity, and basically what we are trying to do with the current study is to see if functional position medicine has a role in adult sarcoma treatment. The specific study that we're conducting is a feasibility study, is trying to evaluate if we can do this, if it's an approach that we can do for adult sarcoma, and ideally to lay grounds for future testing, to see if we can potentially guide treatment in these patients in the future.

Basically, what we are aiming to do is drug sensitivity is a methodology by which we extract cells from the patient's tumor, and we do a genetic profiling, and test many different chemotherapy agents to see how these cells react. Based on a scoring system, we are able to determine if these cells do respond to the different chemotherapy agents. Also, we can combine different chemotherapy agents to see if they have a higher effect, or a lower effect, depending on the combination of drugs.

Dale Shepard, MD, PhD: The genetic testing you're doing, is this something like next generation sequencing? Are you doing a different type of sequencing?

Jorge Manrique-Succar, MD: We're doing next generation sequencing, and we're trying to correlate the genetic mutations, and the genetic profile of those tumors with the response to the different chemotherapy agents to try and come up with a precision, or a much more individualized approach, of chemotherapy for these patients.

Dale Shepard, MD, PhD: Are you looking at specific types of sarcomas? Are you looking at sarcoma in general? Are there subtypes that are being studied?

Jorge Manrique-Succar, MD: We're doing basically this on adults sarcomas. Basically, soft tissue sarcomas given the rarity of the incidence of these type of tumors. We're keeping it broad to try include all of these type of sarcomas.

Dale Shepard, MD, PhD: Some sarcomas we know have fusions, for instance, are associated with them. Are those being included? Are we looking for things that are outside of fusion driven sarcomas?

Jorge Manrique-Succar, MD: Yeah, we're including all of them.

Dale Shepard, MD, PhD: Okay. From a testing standpoint, from the drugs that you're looking at, are you looking at drugs that would ordinarily be considered for treatment of sarcomas? Or are you looking at a wide range of drugs hoping to see something that might be active?

Jorge Manrique-Succar, MD: We're running an array of drugs that are both included in sarcoma treatment currently, and those that are also outside of sarcoma treatment. All of these drugs are FDA approved for cancer treatment, not specifically sarcoma, and so we're basically running about 120 drugs in this testing.

Dale Shepard, MD, PhD: It sounds like there's probably two things that could come from this. You might find a traditional chemotherapy that might be active in particular patients, and make those correlations with the genetics, but you can also find the standard genomic abnormalities, like BRAFs, and things like that. Are you finding many mutations in these sarcoma that would enable you to use standard genomic based therapies?

Jorge Manrique-Succar, MD: Right now, we are at our infancy in the study. We haven't been able to identify anything specifically. We started off a few months ago, so we haven't had any results as of right now.

Dale Shepard, MD, PhD: All right. Well, it's certainly something that we'll be eager to keep an eye on, and maybe we'll have to have a follow up, and talk about the results when they're available.

Jorge Manrique-Succar, MD: Absolutely.

Dale Shepard, MD, PhD: Tell us a little bit about sarcoma care and the sarcoma program at Cleveland Clinic Florida.

Jorge Manrique-Succar, MD: Our sarcoma program started in 2019 in a formal way. We have a very unique team as we are very close to each other, and we communicate very often in regards to the treatment of patients. All patients are discussed over the phone. We have two medical oncologists, two radiation oncologists, a plastic surgeon, and a musculoskeletal radiologist and myself. We also collaborate with Cleveland Clinic main campus in our weekly tumor boards. We have other subspecialties in the clinic that can collaborate with us in other aspects of patient care if needed.

Dale Shepard, MD, PhD: Really, this is a relatively new program. From a very general standpoint, in terms of setting up a program like this, treating a rare disease, needing a lot of different specialists. What were the unique challenges or things that maybe you thought went really well as you tried to set it up? Or maybe things that were a little more problematic than you expected? Maybe if people are listening in, or trying to think about maybe better care for patients with sarcoma, and the nature of that treatment. Any guidance you could provide?

Jorge Manrique-Succar, MD: I think that the most important thing is the willingness of the different specialists to be part of this journey. It's a process. It's a long process that everybody has to be committed to put aside a little bit of their time, to go that extra mile, to provide communication tools, and extra patient care. Obviously, being a new program, having patients trust us and be willing to come in and get treatment in the Cleveland Clinic Florida is one of the biggest challenges.

I think that the fact that we're in the Cleveland Clinic, we are collaborating with Cleveland Clinic Ohio, and having thing that we need for adequate pain and management is key. It's very important to foresee the different challenges in terms of the infrastructure that we have. Although, that hasn't been a very big problem, but just making sure that you do have all the tools that are needed from the different standpoints imaging wise, pathology wise, and all those channels of communication need to be there in order to start a program successfully.

Dale Shepard, MD, PhD: With your program, do you have pathologists locally that are doing most of the reading? Are you collaborating with our pathologists here on main campus?

Jorge Manrique-Succar, MD: Given that we have a world renowned musculoskeletal pathologist at main campus, we send every sample to main campus, whether being biopsied here at the Clinic, or from an outside hospital. By protocol, we send all our samples to main campus to be reviewed and shared at tumor board.

Dale Shepard, MD, PhD: I think that, particularly with rare cancers, that's huge. That's a great model to follow. How's the community acceptance of a new program, and that ability to work with maybe the medical oncologist, and a community to maybe provide the chemotherapy part and having more of the surgical part within your program? Has that been pretty successful so far?

Jorge Manrique-Succar, MD: It has, but the majority of patients have transferred their care to the Cleveland Clinic entirely from the medical oncologist to the radiation oncologist. We're bringing the patient in and providing them with all the resources that we have. In terms of patients having the program here, logistically, we have two other centers that are close by, or relatively close by, down in Miami and up in Gainesville. Having the sarcoma program here at the clinic has benefit the community tremendously, because the patients don't have to travel that far to get their care to Miami or up in Gainesville.

Dale Shepard, MD, PhD: The recent additions to the clinic in the Florida area have really been beneficial to patients with sarcoma it sounds like.

Jorge Manrique-Succar, MD: Yes.

Dale Shepard, MD, PhD: Excellent. What's what's next? What do you see as the gaps that will make this program bigger? More effective? More impactful?

Jorge Manrique-Succar, MD: I think adding additional surgeons when the volume increases would be beneficial. Having a multidisciplinary clinic where we can collaborate in the same exam room, where we can have the medical oncologist, the radiation oncologist, and the orthopedic surgeon. Where I trained, that's how we saw the patients and combined our efforts in the same location. I know that, logistically, is a little bit challenging to accommodate different schedules of the different providers, but I think that's the direction I would like to see the program in a few years, where the patient comes in and sees the different special in a same exam room.

Dale Shepard, MD, PhD: Unfortunately, within sarcoma, clinical trials are too rare, rare disease and rare clinical trials. Are you setting up clinical trials within your program?

Jorge Manrique-Succar, MD: We're open to that. That's an upcoming conversation, as to what the opportunities are, to collaborate with main campus, but definitely open to do that.

Dale Shepard, MD, PhD: Just to take a step back when you talked about sequencing, we talked about sequencing and the setting of your trial that you're setting up. What is your approach to sequencing of patients that are just coming through the program? Are you trying to get next generation sequencing on most of those patients?

Jorge Manrique-Succar, MD: Not if they're not within the study that we're doing. I defer the conversation to the medical oncologist to consider if that's something that an appropriate approach, but it's not a routine component of practice currently.

Dale Shepard, MD, PhD: From a surgical standpoint, what do you find most exciting about where the field is now? Where would you like things to go in terms of, "Is there something from a surgical standpoint that you would like to see change?"

Jorge Manrique-Succar, MD: There's a lot of room, especially in the bone reconstruction aspect of sarcoma and reconstruction of patients. I have a specific interest in robotic application of this type of reconstructions. We have used robotics in the clinic to perform these type of reconstructions in metastatic disease. I think that the incorporation of the robotic technology that is currently being used in joint replacements has a huge field in orthopedic oncology that is to be discovered in and applied in our patients.

Dale Shepard, MD, PhD: We have a fairly diverse group that may be listening. Something that maybe people don't realize is when you're doing surgeries, and you're putting in implants, and things about how customizable all those are. Can you maybe fill people in a little bit about if you're going to be doing a big surgery and a reconstruction, what that might entail?

Jorge Manrique-Succar, MD: Absolutely. In the world of orthopedic oncology, we aim to perform limb preservation, meaning that we, number one, take the tumor out and obtain negative margins. At the same time, preserve the limb and preserve functionality. In that regards, what we need is a good structure. Sometimes, we do have to resect bone. When we do that, there are big voids, and industry has the ability to 3D print implants, or we can get them off the shelf to reconstruct as much bone as we pretty much want to preserve that limb and preserve that functionality. You can go from replacing a whole femur, to replacing half of the pelvis, anchoring the implants to the spine, and so on and so forth. I think that it's in responsibilities of reconstruction with the current technology that we have.

Dale Shepard, MD, PhD: Very good. Well, you've had some excellent insights for us today. Anything else you'd like to add?

Jorge Manrique-Succar, MD: I'm really excited of being part of this new adventure in the Cleveland Clinic Florida of building the sarcoma program. I look forward this as we grow and include more providers to make it one of the most important sarcoma programs in Florida. Very

Dale Shepard, MD, PhD: Very good. Well, thank you for being with us today.

Jorge Manrique-Succar, MD: Thank you, Dr. Shepard.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting Cleveland Clinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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