this is all things cancer the podcast of the national foundation for cancer research hosted by nfc's president and CEO Dr sujan ba Dr ba is a globally recognized cancer research Advocate and Visionary leader all things cancer episodes will explore the hindsight insights and foresight of cancer from research discoveries to Patient Care advances and how nfcr and our collaborators are working to accelerate the process of making cures possible hi I'm Dr sujan ba president and CEO of the national foundation for cancer research welcome to this episode of all things cancer today I'm honored to be joined by Dr Dennis slayman the recipient of the 2024 s Georgie prize for progress in cancer research Dr slayman is a Pioneer in the development of targeted therapies he played an instrumental role for the development of her two targeted antibodies from preclinical studies to proof of concept to the eventual us FDA approval of her septin since its approval in 1998 it has been used to treat nearly 3 million women with breast cancer worldwide as of today we'll discuss his uh groundbreaking work uh the challenges he faced and his thoughts on the future of cancer research let's get started Dr slaman congratulations on receiving the 2024 St Georgia prize for progressing cancer research it's a real honor to be here so um this is our 19th prize ceremony and uh we have a big group of people coming and joining you and celebrating your contribution so what does this mean to you to uh receive this Sur prise well it's it's Rec recognition of the work that that we've been doing and it's no single individual can take credit for work certainly not me but the people I've worked with the teams I work with it it's been great to see that work recognized by our colleagues as something worth uh recognizing and and the impact it's have on it's had on patients so uh it's very gratifying it is a wonderful uh opportunity to recognize your really long-term uh contribution to cancer research and for a big body of uh discoveries seminal discoveries you have made lead to uh drugs that are saving people's uh lives how did you get into the cancer research field I always had a intense interest in biology and that grew in um really in high school but then in college and I went to a small liberal arts college in majored in Biology and became very excited about um basic Science Biology but the school I graduated in was not very big in terms of laboratory science there weren't many Labs there only 620 students in the school full enrollment um and it wasn't until I got to the University of Chicago for graduate work in medical uh school that it became really exciting to apply an understanding or an attempt at understanding the biology and the biology of disease and have that be an approach we took in cancer cancer has been an enormously exciting field it's a very challenging field but the concepts that were available to go from thinking about non-specific therapies nonspecific cytotoxic regimens hoping we killed more bad cells than good cells to changing the field uh in terms of our understanding and thinking about what's broken in an abnormal cell and if we can identify that can we target it so we hit that specifically paranormal cells and um I think the whole field has moved in that direction and it's been wonderful to be some part of that and you played a very important part of this and so from um University of Chicago Medical School and you become from um a faculty at UCLA who uh influenced you the most there during uh your study and fellowship and your career probably the biggest single influence was my graduate student advisor so my PhD adviser was Dr Winston Anderson who was a cell biologist he had trained uh initially at Howard and then he did time in France uh at the pasture and institutes in village weef and then he did some time um with Don faucet at Harvard and then his first faculty job was at the University of Chicago and I was his first graduate stud it was really my first immersion in laboratory science and it was Winston who taught me how to do science who taught me how to look at data critically how you should always be your own worst critic but if the data are telling you something believe it even if everyone else tells you it's wrong that never to have preconceived notions um that you try to make the data fit the notion but instead make sure that your Notions fit whatever the data show you um it was just the whole learning from him of the scientific approach and how to do science is had a great impact on me for my ochre career I share the same sentiment I owe my own career to two wonderful advisers Professor Ting H and Professor Breer Wayan I was Professor Ting's first graduate student when China started to open up um The Graduate uh studies it's a privilege right to be the first of U something and then uh I had uh a wonderful graduate school advisers at the University of Pennsylvania when I came to United States Professor Bradford Willam at the chemistry department and he really um taught me how to be self-reliant and push for um Explorations and if you uh wanted to get Specific Instructions from here or direction from him he would uh keep pushing you to sake think differently keep pushing you until you figure out so that was a wonderful way of guiding me um to think uh openly always uh uh explore the uh unanticipated things I think um be on the box yeah so it's wonderful I know uh you have done a tremendous amount of work helping her seon to get to the market and I I read how hard it was during this process and um you never give up so could you share with us um those uh moments that uh you felt inspired and um you felt challenged well it was an interesting story and an exciting story and we've been given a lot of credit but we've been given credit for pursuing the obvious again from the things Winston taught me and the things you were talking but you believe the data if the data telling you something you continue to pursue so when I had my medical experience in training and I was in the clinic treating patients I noticed that patients with different cancers um at that time cancers were defined by the organ system in which they arose and it was monolithic so it was if you had lung cancer that was one disease if you had breast cancer that was one disease if you had coloral cancer that would all them days and it was Silo and the regimens that were developed for them combinations of cytotoxic therapy occasionally endogen therapy but always directed at the disease as if it's one disease and then you look at the patient you see some do extremely well with those standard approaches and some do very poorly that should have been our first clue that we weren't dealing with a single disease that even within an organ system it's a heterogeneous disease and there are several roads that convert a normal cell to a malignant cell depending on what path has been taken that's what's broken and that's what you should be approaching so the one size fits-all approach doesn't work and at that same time became an understanding about anco as you began to understand that different cancers even within the same organ could follow different molecular Pathways what led you to start investigating the role of Uncle Jens specifically um many PR and Georgia Prize winners have been Pioneers in that field and I learned from them um that there were these genes that are not their they called unle genene but they're not conserved because they cause cancer they're conserved because they regulate growth and when they become altered you have abnormal growth and so that was very logical so we started this study B breakthrough yeah it was it it seemed like an obvious question to ask are these genes altered in human tumors um I think the first paper was of 1984 just looking at expression of enogen in different tumors so we started to collect tumors that were being therapeutically removed for for therapeutic purposes the pathologist would make the diagnosis and then the tissue was disposed of U but as molecular biology came online you could look at things more than just microscopically you could look at it at a molecular level so we took that opportunity to begin to study those genes in various tumors and when we were doing that and going through different groups of tumors we came up on an observation that in breast cancer there was about a group of about 20% of all the breast cancers that had an alteration in one of these genes called her two hr2 and that alteration was Gene amplification this is not an inherited alteration that occurs during the life of the IND idual we still don't know how it occurs but a mistake is made when the Xerox Machinery is copying the DNA it sticks on the part of the genome and makes too many copies of this Gene in a certain percentage of breast cancers well you must wonder what does that mean because it was already known that the Genome of cancer cell was unstable so we had the advantage having started with human tumors of having the clinical data and when we looked at the alteration is present and compared it to the clinical data we found that women whose tumors contain this had a much different outcome when they were treated with the best available standard therapy Unfortunately they recurred more quickly and equally or even more Unfortunately they succumb of disease more often that was our first clue that this was a different subtype of breast cancer and that perhaps this is something we should study back in the laboratory that's how it all got started for us from uh that observation and going to the clinical trials so that's a huge uh undertaking and I um heard that you collaborated with gch even though G Tech tried and wanted to give up wanted to shut it down and you you were the champion and keep it alive well there was challenges that's for sure um there was and it it was a definite collaboration with scientists that gench there was a small group of scientists who really believes in the data that we were producing uh and there was one particular science scientist we first started with was oxel Orrick who had cloned the heru gene he was one of three Laboratories that cloned it the other laboratory was Stuart Aron at the NCI and the third was the dasi yamomoto in Japan independently all clung the same gene coming at it from different angles and what they found is it was a sibling if you will of the EGF receptor so it was a second member of a four member family that were these type one receptor tyos in kineses they sat like antenna on cells and received signals from outside transduc them into the signal transduction Pathway to stimulate cells along growth and differentiation so they caus proliferation and when we found this alteration and that initial collaboration was with oxel and we found that it was associated with a bad outcome the next question was why so so this collaboration between uh academic researchers uh basic science and corporate scientists and come together purely based on the scientific exchange yes exactly that's how it all started there was no exchange of research dollars or anything it was our interest in these genes oxa orc having clone a a group of these genes he actually had six these centors and we were screening all of them when we found the her to alteration in breast cancer so that's a special period of time scientists are encouraged to collaborate and to share so we shared that information with oxel he was very excited about the fact that it was tracking with this aggressive outcome and at the same time we wanted to say could we target the alteration but before we want to know should we target it the first question had to be answered back in the lab and that was is this just a useful flag for aggressive tumors or is it tracking with aggressive tumors because it plays some role in causing that aggressive behavior so we took that question back into the laboratory so we're fortunate to be involved in some research and it wasn't just our lab there are other labs doing things similar where we took the herd 2 Gene and transfected it into breast cancer cells that did not have the alteration and when we did that and compared non-altered to alter we found that they grew more rapidly they were less sensitive to endocrine therapy they were much more metastatic um they were more tumorogenic so that was the clue that it was being it was tracking with these aggressive tumors because it was playing a role and causing that behavior that made it a Target but at the time the only thing you could Target something like that with there were no small molecules yeah against Kinesis or that kise but there were antibodies that have been developed to study the protein so again working with gench and oxel Brian Finley who was sort of their antibody expert at the time sent us a series of antibodies we got some from Genentech we got some from Amgen that was studying the protein and we made some of our own antibodies and we began to test them in cells in culture that expressed it and we found that the antibodies would suppress the growth of those cells in culture and if you had a breast cancer cell that did not have the alteration you could put as much antibod as you wanted on it would not suppress their growth so it was specific so then we did in Vivo studies in mice where xenographs human breast cancer xenographs were growing and if they had the alteration we could suppress the growth and if they didn't they would grow and it was armed with that information that we went to the FDA and asked for permission to start phase one studies that happened at UCLA so it was a very exciting time it is an exciting time how did you get the lawyers from ginch and the UCLA to work together well they weren't at the beginning because jentech didn't think I know this is going to sound crazy but the company had just come off of two uh for one of a better word failures oncology tnf and interferent which were going to be big Cancer drugs but neither one panned out to be be something that we used easily in cancer so the chief medical officer at the time at Genentech said cancer is not a business and it's interesting to hear that from a company like jentech where cancer is their business today but there was a small group in the company that believed in it at that point then oxel left and went to become director at the max plank in Germany uhhuh but there were still some scientists at at Genentech who saw these data and believed that after we saw the found the alteration saw that it track with aggressive outcome and saw that the antibodies could suppress their growth one of those science scientist was Mike sheeper and what we did in collaboration with him was keep the project alive in Genentech even though it wasn't officially promoted within the company as a formal project and that kept it going for the next couple years till we developed more data that showed that it was specific and showed it work so having an internal Champion like Dr shepher is critically important to keeping the project alive ultimately a decision was made to take the mouse monoclinal antibody that we found was most active in suppressing growth and humanizing once it was humanized we could start clinical trials in patients although the first clinical trials were even done with the mouse antibody um really yes that's a very unheard of well at the time time there wasn't humanizing an antibody was in its infancy I see now the problem of giving a mouse antibody to a human is not that you hurt the human but that humans recognize the mouse antibody is foreign and they make an anti-antibody that by the third or fourth time you give the drug it is removed from the system very quickly because it's recognized as a foreign protein so the humanization of the antibody was critical and that was done by Paul Carter uh and Len Presta both of them were a genc at the time and again it was the infancy of that process of how to humanize an antibody when we got to humanize the antibody back we went into patients uh again with the humanized anab body and that's where we first started to see the first activity that we could suppress the growth in patients so I bet um you need comein the some of the patients early on to come on to this uh new um unproven drug and instead of using the traditional chemo yes so that must be um challenge that was a real Challenge and it was a real eye openening experience and it was a personal experience that made me realize that the participants in these clinical trials aren't subjects or just participants but they're colleagues exactly they were invested in answering the question as much as we were um and they came from all over the country for the first phase one clinical Tri there was a group of about 22 women they are unsung heroes yeah start with doses less than we gave a mouse because this is a normal protein expressed in normal tissues and the worry was would we have consequences so we had to start at low Doses and we could not Advance those p to the next dose because we had to make sure there was no long-term safety problem but if they cleared that the next group got a higher dose and um they all participated and when I gave them the informed consent we talked about the fact that this may not help you in fact there may be side effects but it'll help us understand the filled into to a person they signed on and said we understand it may not but it may help the next person and it was a very enlightening and sobering experience they they were true colleagues in the story and I believe some of the uh patients um carried on all the way through the clinical trial so so when we got to the highest doses that's when we started to see the responses that were complete and durable and in fact it was the patients at those highest doses that and the first patient and she's been public about it who uh has been out there was a patient that had widely metastatic disease was told that she had maybe 10 to 12 weeks to live and went on the trial at this higher dose and all of her lesions multiple lesions in the lung multiple lesions and both completely resolved she is now alive 32 years later and at that point J inct began to believe that this possibly could be a real drug C can you imagine that uh at one point they were going to shut down and I think the patience that organizes the campaign also demand to that going right once the phase one data became public and people knew there was a drug there's a whole separate story that The Advocates uh became involved and one of the people who will be at the celebration today is Fran visco who led the National Breast Cancer Coalition she's a real Powerhouse and she's the one that started lobbied the White House and the government to increase funding in breast cancer research became aware of the herto story and also became involved with Genentech pushing them to keep the program going forward so it just shows that this um any successful drug getting on the market it has to be the true collaboration scientists absolutely corporate patients and Patient Advocates as I said it's not one person that does this this is a good Testament for that um journey and and uh um now uh Peron has been on the market for a long time saved um millions of people I we started to see um uh more and more drugs are developed um uh based on that initial uh observation of her two Gene and you see so many ad now I think the last K is about 100 um adcs targeting different targets and exactly and there are mple that are targeting her too maybe four or five two of which are already been approved so her to her to low her to low low but those drugs are not utilized extensively what do you think is the issue I I think the issue in many areas terms of why they're not used this could be cost these drugs are enormously expensive um and then the safety profile has changed to some degree the initial her to antibody was the antibody by itself and it could be given alone or it be given with chemotherapy and it's been approved in both settings the initial approval of the drug with the 25th anniversary was last year so it's been around for 25 years it was first proved in metastatic bre cancer in 1998 and then in 2005 it was approved in early breast cancer and now there are more than 3 million women globally have' been treated with the antibody but there are newer antibodies percept in itself that has a cytotoxic attached to it an ADC an antibody drug conjugate and they have now started to use the kinds of conjugates that could hit even too low well the problem is this genus and the protein is expressed in normal tissue so if you begin to go after her too low and develop the antibody you're going to get more safety signals the initial antibody was very forgiving for safety I see the adc's have gotten more liabilities but they're very effective so you are hopeful for this few do you um feel this is the right directions uh to go and I see more and more people uh utilizing the combination you know this um uh combination of this uh with um um her to combination of that with um uh immunotherapy so many combination uh trials uh going on um and the results are either no good or not durable what what's what are your thoughts on this so there's no question that some of these combination strategies make a lot of sense and uh putting together the right combination of targeted therapy or even targeted therapy with some of the standard approve therapies can be very effective and we're still learning how to do that and do that well um so you're absolutely right that this combination of factors or combination approaches is really going forward in a big way we're learning um how to use the immune system and activate the immune system antibody therapies themselves using the antibody as a therapeutic using it as a drug and then making by specific antibodies yeah and tri be again altering the tea cells in the repertoire of the tea cells and cart teas to direct them to be better uh engineered so they can attack the Cancer all that field is exploded now and again prior St Georgie Prize winners have been involved in some of that like jalis so it's it's an exciting time there's a lot that's going on in a very positive way yeah I just feel um we need to do U Better signs before we do more and more combination thies yeah it shouldn't be just let's throw this combination against the wall and see the work should be based on true signs yeah yes uh and um you know another uh thing is the target therapy you mentioned in certain cases so effective but the utilization of that is less than 40% in us and even worse in other parts of the world what do you think is a barrier for uh the PlayStation medic and targeted therapist uh to be applied well toger uh populations the barriers for applying at the bigger populations are one cost two the effectiveness the degree of impact how much you change outcome should be significant enough enough that it's it is support supports the cost of the drug I see so frequently something will be approved because it was statistically significant the difference but is it clinically significant does it make a big enough impact especially in countries where the government is paying for the drugs so society's paying for the cost of the drug the impact should be big and those the drugs we should be going for not just small incremental changes but large changes a lot needs to be done in that field as well and um you know we are giving uh patients a fifth uh line of therapies what do you think we should do to actually try to stop uh cancer early and uh do you think there is any um um science based early detection early intervention that we should uh focus more now that we had so many uh Therapies in uh you know toolbox already so you're asking a great question and the earlier we can diagnose and in fact if we can prevent the disease understanding prevention strategies would be ideal but in absence of that thinking about how early you can diagnose things and you're aware of this whole idea of now we can test the DNA the circulate so we no longer have to see a tumor or biopsy a tumor but we can detect through abnormal DNA that circulating in the blood the presence of a Cancer and we now refine that enough that when we see certain kinds of patterns it tells us where that cancer may be even if it's not visible yet on the scan so early detections becoming a very big uh area of research that is is real it's it's really paying off so the efforts on early detection and the early intervention in my view are still significantly less than the late stage uh treatment and effort you're absolutely right but it's moving very quickly and it in a good way that's good and um what are are the good advice from you um for the young generation of the scientists and the different types of organizations for collaboration well it's an enormously exciting time for cancer research because the tools we now have available you talked about all the tools available for treatment the tools available for research to interrogate tumors to interrogate cancer cells to do single cell genetics are incredible they changed dramatically just in the last five and 10 years so um you know being able to look at a tissue and do spatial genomics on which cells are having what alterations is is here we can actually do that so it's an exciting time for new investigators starting in this field to learn how to apply those tools and ask and answer even more questions and develop more information that we can improve what we're doing today even beyond the targeted therapies we currently have so what do you think uh is on the horizon for the next breakthrough oh I think an understanding of the microbiome and how the impact of the microbiome might impact what's going on inside the patient is an exciting area of research uh really understanding potential prevention strategies based on what is causing the genetic alterations that occur as you know most all cancer is genetic but only a minority are inherited most are genetic alterations that that occur after uh someone's born in specific tissues and even if you live a perfect life every time a cell divides a mistake can be made and if it's made in the critical genes that regulate growth you can be off to the races with a cancer so understanding what makes those changes happen and and how to better avoid that I think could could really open up the field of prevention wonderful thank you very much D this l thank you once again congratulations it's wonderful to have this opportunity to hear your story hear your challenges and uh um share uh your future views and thank you for having me thank you for joining us for this month's edition of all things cancer please subscribe so you don't miss future episodes learn more about how nfcr is working every day with the cancer research Community to make cures possible at nfc.gov