We're delighted to welcome Dr. Farhia Kabeer as our featured guest, where she shares her expertise on pre-clinical models for research and chemotherapy resistance. Additionally, she highlights some of the promising research projects that aim to enhance treatment strategies and reduce toxicity levels for patients with high-grade serous ovarian cancer.
Bio:
Dr. Farhia Kabeer is a gynae surgeon from Pakistan. Her cancer research took off from MSc at McGill University studying the metastatic potential of breast cancer cells. Farhia’s PhD research encompassed the fields of cancer evolution and translational breast cancer research. She obtained a real-time look at how cancers evolve and why chemotherapies that are initially effective fail over time. Currently, Farhia is a post-doctoral fellow at OVCARE and her work focuses on high-grade serous ovarian cancer pre-clinical models to test novel combinations therapies.
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For more information on the Gynecologic Cancer Initiative, please visit https://gynecancerinitiative.ca/ or email us at info@gynecancerinitiative.ca
Where to learn more about us:
Twitter – @GCI_Cluster
Instagram – @gynecancerinitiative
Facebook – facebook.com/gynecancerinitiative
We're delighted to welcome Dr. Farhia Kabeer as our featured guest, where she shares her expertise on pre-clinical models for research and chemotherapy resistance. Additionally, she highlights some of the promising research projects that aim to enhance treatment strategies and reduce toxicity levels for patients with high-grade serous ovarian cancer.
Bio:
Dr. Farhia Kabeer is a gynae surgeon from Pakistan. Her cancer research took off from MSc at McGill University studying the metastatic potential of breast cancer cells. Farhia’s PhD research encompassed the fields of cancer evolution and translational breast cancer research. She obtained a real-time look at how cancers evolve and why chemotherapies that are initially effective fail over time. Currently, Farhia is a post-doctoral fellow at OVCARE and her work focuses on high-grade serous ovarian cancer pre-clinical models to test novel combinations therapies.
_
For more information on the Gynecologic Cancer Initiative, please visit https://gynecancerinitiative.ca/ or email us at info@gynecancerinitiative.ca
Where to learn more about us:
Twitter – @GCI_Cluster
Instagram – @gynecancerinitiative
Facebook – facebook.com/gynecancerinitiative
SPEAKERS
Stephanie, Farhia
SUMMARY KEYWORDS
high grade serous ovarian cancer, chemoresistance, mice models, pre-clinical studies, gynecological cancers, oncology, British Columbia, podcast, cancer treatment, chemotherapy, side effects
00:00:01 Introduction
Thanks for listening to the GOSH podcast. GOSH stands for the Gynecologic Oncology Sharing Hub, an open space for real and evidence-based discussions on gynecologic cancers. We'll share the stories of gyne cancer patients and survivors and hear from researchers and clinicians who are working behind the scenes to improve the lives of people with gynecologic cancers. Our podcast is produced and recorded on traditional unceded territories of the Musqueam, Squamish, and Tsleil-Waututh Nations. It is produced by the Gynecologic Cancer Initiative, a province-wide initiative in British Columbia with a mission to accelerate transformative research and translational practice on the prevention, detection, treatment, and survivorship of gynecologic cancers.
Hi, I'm Nicole Keay, and I'm Stephanie Lam and you're listening to the GOSH, podcast.
00:00:58 Stephanie
Welcome back to the Gosh podcast. Today we're very excited to have a new guest join us today. Today we're joined by Dr. Farhia Kabeer. Dr. Farhia Kabeer is a gynae surgeon from Pakistan. Her cancer research took off from MSc at McGill University studying the metastatic potential of breast cancer cells. Farhia’s PhD research encompassed the fields of cancer evolution and translational breast cancer research. She obtained a real-time look at how cancers evolve and why chemotherapies that are initially effective fail over time. Currently, Farhia is a post-doctoral fellow at OVCARE and her work focuses on high grade serous ovarian cancer pre-clinical models to test novel combinations therapies.
So welcome to the podcast for Farhia. And why don't we get started and why don't you just tell us a little bit more about your research.
00:01:59 Farhia
Thanks Stephanie. Thanks for having me today.
Yeah. As you said I'm working with Dr. David Huntsman and clinical oncologist Dr. Yvette Drew and my work mainly in focus is a very common subtype of ovarian cancer that's high grade serous ovarian cancer. And because this is very common and most of the patients are diagnosed, they come to the clinic when the cancer is already very advanced. So, I'm very much interested in studying in this case.
00:02:33 Stephanie
I see. what was your interest in gyne cancer. I know that your masters and your PhD work was both in breast cancer. So, what kind of what was your interest in the gynae field?
00:02:49 Farhia
Right, right there are a couple of factors, so I actually graduated as a medical student. Like I'm a medical graduate back from Pakistan and I worked as a physician. I graduated in gynecology and obstetrics.
So, I worked as a gynecologist back home for a few years in a clinic. In a teaching hospital too. So, I was very much inclined to study and cancers in women and in cancer specifically. It's kind of my personal thing because. It's my both parents. They passed away of cancer so I was very keen to go and do some research and do my part in cancer. So, in the beginning I was very much inclined to go for female cancers, and I got a chance to start my research career in cancer starting from breast cancer at McGill. So for both for my Masters and PhD I worked on breast cancer and how they become resistant to chemotherapy. Because from my experience my personal family experience and looking in the clinic to other patients. The main problem in cancer field is that the patients come with recurrence. They come with drug resistance, so that was always bothering me. I wanted to do in that field like why cancer cells they become resistant. And because of my interest and my clinical practice in gynecological field, I was much more inclined. And honestly, I find a very good team of OVCARE and GCI in BC. Especially when I was doing my PhD at UBC, I found this group is a very good team to work with. I planned to join OVCARE and Gynecological Cancer initiative team to pursue my post-doctoral training.
00:05:03 Stephanie
Yeah no, that's amazing. Thank you so much for sharing all of that earlier. You mentioned how cancers become resistant, so can you just break that down a little bit more for our listeners? Like what do you mean when we say that cancers become resistant?
00:05:22 Farhia
OK, that's a very good question.
Yeah, because we always talk about resistance and many of the people, they don't know what is meant by resistance.
So resistance, in a very simple words, I would say like what happened when first time patient diagnosed with cancer. And then the clinicians start chemotherapy or some drugs to shrink down the tumor burden. And at some point the tumor goes away completely. But after some time even if the patients are taking those drugs. The tumor came back and this time the tumors are not responding to that treatment. That means the cells are no more responsive to that treatment that the cells are resistant to that drug specifically. Then we try another drug. We start with the conventional (therapies) first line chemotherapies that is like for decades given to the patients. But now with the new advances in technologies we have new drugs that are in the in the clinical trials and already in clinical practice that are known as targeted therapy. But unfortunately, what happens after certain time period, those tumors and those cells, they also become nonresponsive to those targeted therapies. So that means when the tumorsare not responding to those treatment the tumor we label them as a resistant tumor.
The tumor is still growing. They have not stopped growing. They are not shrinking. In both cases we call them resistant.
00:07:20 Stephanie
I see thank you for breaking that down. That's a really kind of good basics for our listeners just to understand a little bit more about your work. So in your current work right now, you work on preclinical models and I think more specifically you do some work with mouse models. So I'm curious if you can talk more about what preclinical models are? How they are being used in guiding cancer research and why they're so important?
00:07:53 Farhia
Yes, yes Stephanie, for you and other listeners that's very important to understand.
Like how we conduct research and we really need very advanced and specialized models to test different drugs, their combinations, their formulations and their doses that we cannot test in human directly because of ethics. Under strict animal ethical protocols, we have now developed different kinds of models that we can study in mice. There are other species we can study, but specifically what I'm studying right now are mouse models. There is much evidence that says that mouse models are very close to humans. Not exactly but they're very close because they allow you to create expert experimental designs and set where you can test tolerability right in different forms of preclinical work. So how can we make these preclinical models. We can create them by taking the patients tumors and their normal cells. We stabilize these cells, and we make them quite competent in the plastic dishes, and then we take those cells and we put them in animals either under the skin of a mouse or in the abdomen of mice. So they can develop. They can let those cells grow in them. And these are PDX model, which is much closer to the patient. PDX stands for patient derived xenographs model. That means we take patients original tumor, and we put them in the mouse.
I and many other groups all over the world have tested that PDX's are very close to the patients original tumor. How we do that? There are different routes, and it also depends on the type of cancer you want to study. Some people when they are studying brain cancers, they put the tumor directly in the brain. Some people study breast cancer. So they put the tumor directly onto the mouse breast. I'm studying high grade serous ovarian cancer So what I do I take patients tumor and put in the abdomen because ovaries are inside the abdomen. But then you have to track the tumor. Another thing is you can put orthotopic, you can put the tumors under the mouse’s skin. So you can directly look and measure the tumor on mouse skin and then you can test different combinations of drugs chemotherapy. You can measure the tumor response directly with the caliper and see how much the tumor is responsive to chemotherapies. And if you are trying some new targeted therapies, this is the best thing to test first before going to the patients.
00:11:17 Stephanie
Why is it so important in gyne cancer research?
00:11:21 Farhia
Right, that's the thing, because gyne cancers most of the times are diagnosed at a very little later stage. In the mouse in preclinical models you can divide and you can assign different time points to your experiment and you can track the tumor according to your own time period. Like if you want to study and biopsy a tumor after three weeks, you have the liberty to do that in your preclinical mouse models and you can take repeated biopsy. But I'm repeating again, these are all after mouse and animal ethics approval. There is a full committee, canadian animal committee that allow all these experiments. They approve that and then only we performed that. Tt's very, very helpful, because then you can even test different doses because there is special way to convert mouse dose into human dose. We cannot test different new drugs when they come into the clinic. We don't know how much to give to the patients, how much side effects to anticipate. But in animal model and preclinical model you can test different doses accordingly. So, like they are very close to the human patients and they are very useful to work with before the clinical trial.
00:13:10 Stephanie
Yeah, no, that's a really great point. I think just to add on for our listener. I think like you kind of mentioned, doing clinical trials is a really expensive, really time consuming and costly sort of procedure. So this is a really great way to kind of test out hypotheses that scientists have, test out new treatments before they get to a stage where a lot of money needs to be put into building and executing clinical trials. So thank you for that explanation.
You kind of touched on this a little bit before when you were talking about what resistance means, but in your studies around the evolution of cancer, how exactly do these cancer cells become resistant to chemotherapy?
00:14:03 Farhia
Yes, this is a very important question. Umm honestly, there are multiple mechanisms operating behind this resistance to chemotherapy and resistance to drugs in the clinic. So I will just briefly and simply for the listeners I would say like now we have very advanced technologies where we can look into DNA. We can look into RNAs. We can look into different kinds of proteins and now we have cutting-edge technologies of doing single cell sequencing. So we can directly zoom in into each cell of the tumor, which is quite amazing. I am so thankful to all the doners and all the patients that are giving consent to study their tumor. Honestly these things are helping us a lot.
So what we have done so far is to look into what happens once the patient come into the clinic we gave them chemotherapy and any drugs. So every time we are giving them the drug or the treatment or if we are not giving them, even in the absence, as the tumor grows, there are certain changes. There are certain population of cells within the tumor that fluctuate some of the cells they grow and some of the cells they shrink. Right, it depends on the environment. If the cells are much more fit in that environment, they will grow. The fitness of these cells to grow depends on multiple factors. So it could be the microenvironment that is much more feasible. So far we have detected many different kind of mutations in the genes and they are very well documented, very well known. If the cells are having this type of mutation we can target it for example, or we cannot target it, or this will come with resistant to these drugs. So there are certain changes in the genes and as the tumor grows further, more mutations. When we treat the tumors with the drugs, it becomes it advanced. There's another layer of complication, some medication are lethal for some of the cells. They go away, but some of the cells will develop some more kind of mutations. It's not only the story of mutation in the DNA in the genes. There could be a functional protein is disturbed. So it's not only one mechanism that is operating and causing the resistance. Otherwise, it could be very easy to treat, but there's multiple mechanisms like DNA level, protein level, RNA level, and now there is another field of epigenetics I don't want to go into these more detail of these technical terms, and then patients own immune system. This is another factor that is contributing. Sometimes it's beneficial. Sometimes it helps in causing more resistance. So there are multiple factors. Patients’ diet. You know how the living style. the living environment. These are just additional factor.
00:17:30 Stephanie
Yeah. That makes a lot of sense. It's such a complicated topic and so many different things impacting it all at once. And I can definitely see how that it's not a simple or straightforward answer by any means. So now I'm coming up to my very last question. I'd love to hear more about what sorts of projects you're working on right now in the area of high grade serous ovarian cancer. So just give us a little overview of what you're working on right now.
00:18:03 Farhia
Sure, so first of all, I talked about the clinical trial that Dr. Yvette Drew will be starting soon, and we are just in the final process of some documentations. This is what I mentioned. Usually what happens in the clinic. Since decades and decades, when the patients with any kind of cancer patient when they report to the clinic they are put to the first line of treatment that is chemotherapy, conventional chemotherapy, regardless of the cancer type. And they are cytotoxic drugs and the patients they experience a lot of side effects of that and hair loss and many others.
But now this clinical trial, which is I'm also involved in, and I will be receiving patient samples soon. It's based on the first line treatment with the targeted therapy that are non-cytotoxic therapy. So there has been a little clinical trial done in UK. Dr. Drew, like my mentor with whom I'm working with. She will be starting that trial soon. So if you're aware of a little bit of the BRACA mutation. Most of the high grade serous cancers do have this mutation. So far it's well established at the targeted therapy it has a very good effect in the tumors having BRCA mutation are having very good response to PARP inhibitor and all the patients are usually put on this therapy.
So what this clinical trial is going to do? This PARP inhibitor will be given as the first line of treatment, rather than the second line of treatment in the clinic to the selected patients.
Along with additionally 2 more targeted therapy drugs, so one drug would be targeting the blood vessels because you know when the tumor or cancer grow, there is development of new blood vessels within the tumor. Cancer is not one disease that we always say that it's not only the cancer cells that are problematic. They need oxygen and nutrition to grow, which is provided by the blood vessels. So we are planning to put the targeted drug which will target these blood vessels not to form them. And along with that, another drug that will target the immune system specific targets on the immune system. So this clinical trial would be a combination of three targeted therapy three drugs that are non-cytotoxic. I will emphasize again, they will not be showing those cytotoxic effects in the patients. So these will be given as a first line treatment. I'm so excited for these trials and hoping good results.
So we will be receiving pre surgical tumors like the biopsy samples. Then during the treatment I will be receiving blood or static fluid or any material and once the treatment is finished then if there are any residual tumor or any blood sample. I will be looking at that and I'll try to develop some PDX and some preclinical models. I will try to grow these tumors in mice and use translational work and look into the DNA and RNA of those materials and to anticipate and look for how the resistance could develop towards these combination or how what are the changes at the DNA and RNA level. Main project I am looking forward to.
Other than that, because this trial has to be started, so far I have tested these three drugs in preclinical model in the mice. So I made six different groups of mice, six different cohorts, and I tried these drugs and I found that as compared to other drugs, these three, the combination as compared to vehicle and as compared to PARP inhibitor alone, the combination of these three drugs as a first line of treatment even regardless of the BRCA status. That's the important point because so far we are giving our inhibitor Olaparib only to the patients that are diagnosed with BRCA mutation. But these three what we hypothesized that regardless of the BRCA status. If we give these targeted therapy data, the tumors will respond better or with less toxicity, less side effects, and that's put the patients. We talked to some patients actually and they were so excited. We definitely need to change something that is going on in the clinic. We should try at least. Because this conventional chemotherapy the cytotoxic therapy is for around 50 years going on.
00:23:19 Stephanie
Yeah, yeah no, that's so exciting. We always hear from patients how much of an impact the side effects are to their quality of life during treatment. But then also after treatment. So I think this work that you and Dr. Drew are doing is really exciting step for this field.
00:23:48 Farhia
Yeah, thank you very much. Also I'm receiving right now patients tumors from Vancouver General Hospital that are untreated. So I'm taking that tumor processing them and creating these preclinical models to test how much they are similar to patients original tumor and I am treating them continuously and trying to make them resistant myself. So if you treat that tumor repeatedly once at one stage, they will become resistant. So I'm also working on these patient derived grafts to see what are making them resistance. And then I'm studying different mechanisms of resistance in them looking at the DNA and RNA level. At single cell level.
00:24:38 Stephanie
Umm, that's really interesting, there's lots of exciting projects going on and such a wide variety. I know for sure your work is kind of much more at the molecular level, a lot of translational work, but also your involvement in the clinical trials and trying to be really actively with the administration of new treatments. New therapeutics is really exciting. So thank you so much for sharing all of your wonderful work.
And just for dissecting a little bit more about this topic to our listeners here today, I think there's a lot of scientific jargon that is often used even to patients. And I think just breaking it down today, really was able to explain things in a really easy to understand way, so thank you so much for sharing your work and for coming onto the podcast and just being part of this community here in BC.
00:25:44 Farhia
Thank you very much for having me! Have a good day!
00:25:46 Stephanie
You too! Bye!
00:25:50 Outro
Thanks for joining us on the GOSH podcast! To learn more about the Gynaecologic Cancer Initiative and our podcast, make sure to check out our website at gynecancerinitiative.ca.