The Association of PBAF Complex Mutations with Overall Survival in Cancer Patients Treated with Checkpoint Inhibitors - Sarah Abou Alaiwi
July 30, 2019
Sarah Abou Alaiwi, MD discusses her recently presented bench to bedside research with Monty Pal, MD. She explains that PBRM1 is frequently mutated around 40% on Renal Cell Carcinoma. It is part of this Mammalian SWI/SNF complex, which is really what drove interest in this complex. This complex is really huge. It has 29 subunits. It's frequently mutated in around 20% of all human cancers.
There is preclinical and clinical evidence, which implicates mutations within this complex and responds to treatments with immune checkpoint blockade (ICIs). In our work, we look at the extreme population, so that's really a loss of function mutations within this complex. What we got to learn is very intriguing because, in terms of survival at least, mutations within the Mammalian SWI/SNF complex were associated with better survival outcomes in renal cell carcinoma and colorectal carcinoma. But it was actually associated with worse survival in non-small cell lung cancer. The results shed light on the disease-specific function of this complex.
Biographies:
Sarah Abou Alaiwi, MD, Fellow at Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States
Sumanta Kumar Pal, MD, Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research, Co-director Kidney Cancer Program, Medical Oncologist, City of Hope, Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA.
There is preclinical and clinical evidence, which implicates mutations within this complex and responds to treatments with immune checkpoint blockade (ICIs). In our work, we look at the extreme population, so that's really a loss of function mutations within this complex. What we got to learn is very intriguing because, in terms of survival at least, mutations within the Mammalian SWI/SNF complex were associated with better survival outcomes in renal cell carcinoma and colorectal carcinoma. But it was actually associated with worse survival in non-small cell lung cancer. The results shed light on the disease-specific function of this complex.
Biographies:
Sarah Abou Alaiwi, MD, Fellow at Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States
Sumanta Kumar Pal, MD, Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research, Co-director Kidney Cancer Program, Medical Oncologist, City of Hope, Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA.
Read the Full Video Transcript
Sumanta Pal: Hi, I'm Monty Pal, the medical oncologist at the City of Hope Comprehensive Cancer Center Los Angeles and we're here today on behalf of UroToday with a rising star in the field, actually a star already, Dr. Sarah Abou Alaiwi, who's a fellow at the Dana Farber Cancer Institute. Sarah, welcome.
Sarah Alaiwi: Thank you so much Monty, it's so nice of you to have me here.
Sumanta Pal: Oh, it's my pleasure. Well, I've got to talk a little bit about what I know of you first. So this is your first ASCO meeting. You've arrived from Beirut to work with the legend in kidney cancer, Toni Choueiri, for a year-long span. My understanding is that at your first ASCO meeting, you're already gracing the podium. Tell me, how did this all come about?
Sarah Alaiwi: Well, thank you so much, Monty, for your kind words. Actually, I came here after graduating from medical school last year. My husband was actually working with Toni Choueiri and David Kwiatkowski at Dana Farber. And so I got to meet him and they got me on board. It's been fantastic so far like I just can't describe the type of research I get to do. I work with fantastic people, really brilliant people. And I've been lucky actually to be here today.
Sumanta Pal: That's fantastic. Well, I've got to ask you about Tony's mentoring approach. So just to let you know, I consider Tony to be a mentor from afar. He's 2500 miles away from me, but he's 8000 miles away from Beirut, and he's your mentor. What's it like now that you get to work with him day to day?
Sarah Alaiwi: If you know Tony, you know he's a ball of energy. I just can't describe the energy and the positivity he has. And you'd expect someone in his position to be super busy, but he always makes time for us. And he's always there, I can call him or text him anytime, and it feels great because they type of advice he gives you, you know it's focused on your career. It's just not for today or tomorrow. He truly advises you to be the best of your capability and he truly makes sure we're always okay, mentally and at work. I feel like he drives you. Regardless, if we put aside the scientific advice he gives you on a day to day basis, just watching him work is so much motivation because he makes you love your work and you get to learn so many good things from him.
Sumanta Pal: Monty Pal: Oh, that's fantastic. I just don't know how he does it.
Sarah Alaiwi: Right?
Sumanta Pal: I mean he's up on the podium all the time. He's on Twitter all the time. He's a family man too. It's remarkable how he strikes that great balance.
Sarah Alaiwi: I mean you get to learn a lot. Working with Toni, I don't think anybody can do it, to be honest. He has so much energy and so much drive. Because I feel like, because how much he loves his job, it comes naturally to him. He doesn't even have to force himself to do anything, it just comes out naturally. He's such a great example of how you can strike that brilliant balance between workload and life.
Sumanta Pal: And tell me about your day to day at the Dana Farber? What do, are you in the lab, for the most part, the clinics, or a mix of the two?
Sarah Alaiwi: I mostly work in Matt Friedman lab. And our research is mostly focused on epigenetics, so it's mostly translation on basic science research. I spend most of my time in the lab, on the bench, actually doing experiments.
Sumanta Pal: Wow.
Sarah Alaiwi: Yes.
Sumanta Pal: That's fantastic. What a great experience. And beyond that, I guess that's sort of a great segway into the work that you presented today, which is a wonderful example of bench to bedside. I was very curious to know what sort of associations you found between these genetic abnormalities and response to IO. You want to give us a little preview of that?
Sarah Alaiwi: Of course. Well, thank you for asking. Actually, we were very interested in the Mammalian SWI/SNF complex, because I work, from at least based on my experience, I really work in RCC domain. You know that PBRM1 is really frequently mutated around 40% on RCC. It is part of this Mammalian SWI/SNF complex, which is really what drove our interest in this complex. What we got to learn along the way is pretty interesting. This complex is really huge. It has 29 subunits. It's frequently mutated in around 20% of all human cancers.
So what was interesting to us is the fact that really there was a lot of preclinical and clinical evidence, which implicates mutations within this complex and responds to checkpoint blockade. What we thought to do is basically look at mutations within the different genes belonging to this complex and responds to checkpoint blockade.
Just a brief overview, this complex had been subdivided into three different subcomplexes, the PBAF, the BAF, and the noncanonical BAF. What we did in our work is basically look at the six most frequently mutated genes in this huge complex, the PBRM1, and the AR2 which belong to the PBAF, and the ARD1 A and the ARD1 B, which belonged to the BAF and the SMARCA4 and SMARCB1, which are common to both complexes.
The results we had were very intriguing. We had, of 17,000 patients at Dana Farber with onco panel testings, so they had tumor sequence, we had 676 patients who were either mutants or wild types. In our work, we look at the extreme population, so that's really a loss of function mutations within this complex. What we got to learn is very intriguing because, in terms of survival at least, mutations within the Mammalian SWI/SNF complex were associated with better survival outcomes in renal cell carcinoma and colorectal carcinoma. But it was actually associated with worse survival in non-small cell lung cancer.
That was pretty intriguing because it really shed light on the disease-specific function of this complex. We are yet to find out more about the intricacy and the complexity and the specific action of this complex in its regulation of the tumor biology in the setting of checkpoint blockade.
Sumanta Pal: That's so interesting because we'd love to have this sort of disease agnostic biomarker for this stuff. But it seems as though it's a little bit trickier than that. This was your first interview on camera at your first ASCO meeting for doing your first every oral presentation. I think you nailed it. I'm very, very happy and proud of you.
Sarah Alaiwi: Thank you so much.
Sumanta Pal: Thanks for joining us.
Sarah Alaiwi: It means a lot really.
Sumanta Pal: Hi, I'm Monty Pal, the medical oncologist at the City of Hope Comprehensive Cancer Center Los Angeles and we're here today on behalf of UroToday with a rising star in the field, actually a star already, Dr. Sarah Abou Alaiwi, who's a fellow at the Dana Farber Cancer Institute. Sarah, welcome.
Sarah Alaiwi: Thank you so much Monty, it's so nice of you to have me here.
Sumanta Pal: Oh, it's my pleasure. Well, I've got to talk a little bit about what I know of you first. So this is your first ASCO meeting. You've arrived from Beirut to work with the legend in kidney cancer, Toni Choueiri, for a year-long span. My understanding is that at your first ASCO meeting, you're already gracing the podium. Tell me, how did this all come about?
Sarah Alaiwi: Well, thank you so much, Monty, for your kind words. Actually, I came here after graduating from medical school last year. My husband was actually working with Toni Choueiri and David Kwiatkowski at Dana Farber. And so I got to meet him and they got me on board. It's been fantastic so far like I just can't describe the type of research I get to do. I work with fantastic people, really brilliant people. And I've been lucky actually to be here today.
Sumanta Pal: That's fantastic. Well, I've got to ask you about Tony's mentoring approach. So just to let you know, I consider Tony to be a mentor from afar. He's 2500 miles away from me, but he's 8000 miles away from Beirut, and he's your mentor. What's it like now that you get to work with him day to day?
Sarah Alaiwi: If you know Tony, you know he's a ball of energy. I just can't describe the energy and the positivity he has. And you'd expect someone in his position to be super busy, but he always makes time for us. And he's always there, I can call him or text him anytime, and it feels great because they type of advice he gives you, you know it's focused on your career. It's just not for today or tomorrow. He truly advises you to be the best of your capability and he truly makes sure we're always okay, mentally and at work. I feel like he drives you. Regardless, if we put aside the scientific advice he gives you on a day to day basis, just watching him work is so much motivation because he makes you love your work and you get to learn so many good things from him.
Sumanta Pal: Monty Pal: Oh, that's fantastic. I just don't know how he does it.
Sarah Alaiwi: Right?
Sumanta Pal: I mean he's up on the podium all the time. He's on Twitter all the time. He's a family man too. It's remarkable how he strikes that great balance.
Sarah Alaiwi: I mean you get to learn a lot. Working with Toni, I don't think anybody can do it, to be honest. He has so much energy and so much drive. Because I feel like, because how much he loves his job, it comes naturally to him. He doesn't even have to force himself to do anything, it just comes out naturally. He's such a great example of how you can strike that brilliant balance between workload and life.
Sumanta Pal: And tell me about your day to day at the Dana Farber? What do, are you in the lab, for the most part, the clinics, or a mix of the two?
Sarah Alaiwi: I mostly work in Matt Friedman lab. And our research is mostly focused on epigenetics, so it's mostly translation on basic science research. I spend most of my time in the lab, on the bench, actually doing experiments.
Sumanta Pal: Wow.
Sarah Alaiwi: Yes.
Sumanta Pal: That's fantastic. What a great experience. And beyond that, I guess that's sort of a great segway into the work that you presented today, which is a wonderful example of bench to bedside. I was very curious to know what sort of associations you found between these genetic abnormalities and response to IO. You want to give us a little preview of that?
Sarah Alaiwi: Of course. Well, thank you for asking. Actually, we were very interested in the Mammalian SWI/SNF complex, because I work, from at least based on my experience, I really work in RCC domain. You know that PBRM1 is really frequently mutated around 40% on RCC. It is part of this Mammalian SWI/SNF complex, which is really what drove our interest in this complex. What we got to learn along the way is pretty interesting. This complex is really huge. It has 29 subunits. It's frequently mutated in around 20% of all human cancers.
So what was interesting to us is the fact that really there was a lot of preclinical and clinical evidence, which implicates mutations within this complex and responds to checkpoint blockade. What we thought to do is basically look at mutations within the different genes belonging to this complex and responds to checkpoint blockade.
Just a brief overview, this complex had been subdivided into three different subcomplexes, the PBAF, the BAF, and the noncanonical BAF. What we did in our work is basically look at the six most frequently mutated genes in this huge complex, the PBRM1, and the AR2 which belong to the PBAF, and the ARD1 A and the ARD1 B, which belonged to the BAF and the SMARCA4 and SMARCB1, which are common to both complexes.
The results we had were very intriguing. We had, of 17,000 patients at Dana Farber with onco panel testings, so they had tumor sequence, we had 676 patients who were either mutants or wild types. In our work, we look at the extreme population, so that's really a loss of function mutations within this complex. What we got to learn is very intriguing because, in terms of survival at least, mutations within the Mammalian SWI/SNF complex were associated with better survival outcomes in renal cell carcinoma and colorectal carcinoma. But it was actually associated with worse survival in non-small cell lung cancer.
That was pretty intriguing because it really shed light on the disease-specific function of this complex. We are yet to find out more about the intricacy and the complexity and the specific action of this complex in its regulation of the tumor biology in the setting of checkpoint blockade.
Sumanta Pal: That's so interesting because we'd love to have this sort of disease agnostic biomarker for this stuff. But it seems as though it's a little bit trickier than that. This was your first interview on camera at your first ASCO meeting for doing your first every oral presentation. I think you nailed it. I'm very, very happy and proud of you.
Sarah Alaiwi: Thank you so much.
Sumanta Pal: Thanks for joining us.
Sarah Alaiwi: It means a lot really.