Deirdre Cohen, MD, MS, in a Grand Rounds presentation on pancreatic cancer, particularly adenocarcinoma, focuses on incidence and mortality, challenges to effective therapy, current systemic therapy, promising strategies for novel systemic therapy, and priorities for the future.
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Overview of Presentation Incidence and Mortality Challenges and Effective Therapy Systemic Therapy for Advanced Pancreatic Cance Development of New Therapies and Drugs Based on Precision Medicine Emerging Strategies Future Progress
Good morning everyone. Welcome to Grand rounds. My pleasure to introduce dr Deirdre Cohen, who graduated from Medical school from suny downstate and then went on to complete her internal medicine residency at new york presbyterian Hospital Weill Cornell. She then completed her hematology oncology fellowship at N. Y. U. Where she also earned a master's degree in clinical investigation. She previously served on faculty at the Pearl Moderate Cancer Center, where she was also the medical director of the Clinical Trials office. And then Dr Cohen joined Mount Sinai last year, is associate professor in the division of hematology oncology and director of the GI oncology program for the Health System and Clinical Trials office at the Tisch Cancer Institute. Dr Cohen conducts research focused on immune targeted strategies and biomarker driven studies with translational endpoints and serves as principal investigators on many clinical trials pertaining to novel therapeutic approaches for patients with gi malignancies. A very warm welcome to Dr Cohen today. Thank you Emily. I appreciate the introduction and thank you dr thomas for the invitation to speak today. Um So I'm going to be talking about pancreas, cancer and specifically adenocarcinoma as opposed to neuro endocrine or other types of cancers of the pancreas. And I'll be speaking about the current challenges and some of the future directions with an eye on making the impossible possible. Mhm. There we go. So this is just my disclosures. Um so the learning objectives are twofold. First, we're going to uh describe the current challenges in the treatment of pancreatic cancer and then move on to providing evidence for emerging treatment paradigms. Yeah, here you see the outline for today's talk first, I'll be talking about the incidents and mortality rates. Following be talking about challenges to effective therapy, touching on current systemic therapy and then rounding out with some of the novel treatments that are in development as well as priorities for the future. So, um the incidents of pancreas cancer world worldwide has doubled over the last 25 years. Um and in 2018 there were nearly 460,000 cases diagnosed. Um certainly age is one of the biggest risk factors, as we know that the population overall uh is increasing um in terms of the portion of um People in their 6th, 7th and 8th decades. However, um even when you adjust for age, you can see that the incident is still rising with 5, 400,000 cases diagnosed in 1990 and that increased to 5.7 400,000 years in 2017. So it's really reflecting the fact that there's more to it than age. And I just thought that, you know, the changing prevalence of modifiable risk factors such as diabetes, smoking and obesity are playing a role as well as the fact that we are getting a little bit better at diagnosing pancreatic cancer, especially in developing countries. So, looking at the us specifically in this year, over 60,000, new cases will be diagnosed with over 46,000 deaths and the incidence rate is rising here in the United States, anywhere between .5 to 1% per year. Right, right now, pancreas cancer comprises 3% of all cancers diagnosed in the United States, but 8% of cancer deaths. And it is staged for stage, the has the lowest survival rate of any major cancer. So like the big four, so colon, breast and lung cancer, pancreas cancer as I alluded to is increasing in instance. However, unlike these four cancers, it is not decreasing in mortality rates, but rather increasing and it's on track to become the number two uh, Cause of cancer related death by 2030. Um, and this is really primarily because advancements in pancreatic cancer treatment and diagnosis are lagging behind all of the other cancers. So here you see, part of the problem is the fact that patients present very rarely minority of cases with localized disease. Um, in general, patients are presenting with either regional or distant spread. And you can see the effect that has on Five year survival rates in the bottom panel. So those who present with localized disease have a five-year survival of 42% and this drops down to 3% with distant disease. Looking at all comers, the overall five year survival rate is now 10%. And well, of course this certainly sounds dismal. I will note that in the 1980s, this number was 4%. So there have been some small incremental benefits that have been gained. But certainly we haven't made a huge jump in the trajectory of this disease. So why is that? I think, you know, there's really it's twofold. There are clinical challenges which as I alluded to include the late uh an advanced presentation. You know, patients present with very vague symptoms as the pancreas law is deep in the retro peritoneum. There's also significant limitations on our current imaging modalities. And we have no adequate screening tests to diagnose pancreatic cancer early. We also know that uh pancreatic cancer has a very rapid tumor growth and metastasis. And often um when we first meet patients diagnosed with pancreas cancer there too ill to even receive effective therapy at that time. Mhm. So when patients are diagnosed at an early stage, even at that point, there is still a very high risk of recurrence following surgery, upwards of 70%. And we know from preclinical models that pancreas cancer progression has been shown to see distant organs even before and in parallel to tumor formation at the primary site when compared to other solid tumors, there is a relative resistance to conventional therapy and pancreatic cancer. And finally, there are a few predictive biomarkers to guide treatment, although that is changing and I'll touch on that. Okay, the other problem in pancreatic cancer are the biologic challenges. And so there's an inherent complexity of this tumor with complex molecular characteristics, most notably KRS. Driver mutations, which lead to metabolic dis regulation. There's also a very dismal plastic tumor micro environment that really can act as a true physical barrier to our treatments. And finally, the micro environment of pancreatic cancer is quite immunosuppressive with a paucity of tumor infiltrating T cells and an abundance of mylar derived suppress ourselves to pancreatic cancer develops from precursor lesions known as panas or pancreatic intra epithelial hyperplasia and pan and um progress in a step wide wise fashion um with the accumulation of various genetic alterations and you can see over the course of uh their progression, they develop increasing psychologic and architectural a tibia. As shown here on the bottom here, you can see a cartoon of the various molecular alterations in pancreas pancreas cancer. And you see in the green dot the most um commonly altered oncogene KRS. And more than 90% of us. And then in the red circles the various tumor suppressor genes with high prevalence including p 53 CD. Can to a mad for arid one A. And B. As well as the DNA damage response genes, ATM and Baraka too. But there are many other mutations with high variability and low prevalence and pancreas cancer which with each time you are harboring anywhere between 60-80 mutations which are very different from one to the other. But they do seem to converge on some common pathways and processes as seen here on the right what is very characteristic of pancreatic cancer is the inflammatory context in which it develops. And this is not an acute inflammation but which which you would see in wound healing but rather a self sustaining and unregulated cancer. Self permissive inflammation. And what's interesting is that not only is inflammation a key factor, but it's actually necessary for pancreatic uncle genesis. So keras mutation is not sufficient without this inflammatory context. Again highlighting the importance of uh the inflammatory milieu in this disease. In addition to inflammation, Desmond place that says my pleasure is also very characteristic. And in fact pancreas cancer is one of the most strong mineral rich cancers with many times the structural components far exceeding that of the cancer cells themselves. And here you see histological sections from a normal patient compared with that from a pancreatic uh tumor. And you see the significant strom and fibrosis um that is characteristic of this disease. Sure. So here's a cartoon of the tumor micro environment of the pancreas, pancreas cancer. And what you'll note is in addition of course, to the cancer cells themselves, there are many other components including immune cells, uh hela cells, blood vessels, microbiome including uh bacteria, fungi, viruses. Um and um blood vessels and this environment is really a dynamic entity um which is ever changing. And his um most notable um to change in composition when progressing from a precursor Panin lesion, too invasive pancreas cancer. And so in the presence of anca genic mutations. These genetically altered epithelial cells signal to the various components really creating a micro environment with right for cancer progression with significant extra cellular matrix hypoxia and metabolic reprogramming as well as communist oppression. Yeah. So with that background, you know, it's not surprising how the current approved therapies for this disease are rather disappointing. And so when we look at sort of the treatment paradigms of pancreas cancer, they can be divided into two main stays. So surgery and systemic therapy. And I think this is really a helpful depiction to try to understand um how we look at patients and their tumors for candidacy for surgical resection. And it really depends on the contact with the major venus and arterial blood supply coursing through or behind the pancreas. Um And so we characterize this as as the um are either um uninvolved or a budding or encasing the vasculature. And in in clinical terms we uh term these patients as either respectable borderline, respectable or locally advanced here you see um a sort of summary slide of the approaches to treatment and pancreas cancer based on surgical respectability and so on the left. You'll see that for those patients with respectable US treatment is focused on multi modality therapy with chemotherapy. Either before or after surgery for those patients with borderline or locally advanced disease. Treatment is again multi modality with chemotherapy plus or minus radiotherapy with really the goal to uh minimize the contact or completely remove contact of the tumor from the vessels and enable um surgical resection. And then finally on the right with distant metastatic spread. The goal is really treatment with um palliative chemotherapy to control and prolong overall survival. So now let's move on to systemic therapy for advanced pancreas cancer. And when we when we look back at the key developments over the last 25 years in 1997 is when Jim said rabin was first determined to be a standard of care therapy for this disease. And this approval was based on the study looking at one side of being compared to five floor uracil with the primary endpoint of clinical benefit response which was really a composite measure of pain um functional status and weight. And you can see that compared to five a few. There was a significant increase in clinical benefit. There also was a modest survival benefit seen with median survival of 5.6 months compared to 4.3 months. So this study really set the kind of backbone for the next decade in which Jim said rabin was then combined with scores of different agents um sort of in a metoo way um to see if any combination therapies would improve single agent efficacy. And you can see Jim side of being was looked at in combination with floor permitting Platinums and various antibody therapies. Um But it really wasn't until a decade later in 2000 and seven with this study uh jump side of being with or without a lot in it, which is an oral uh tyrosine kinase inhibitor of E. G fr where there was a statistically significant although questionably clinically significant improvement in overall survival. So the hazard ratio was 70.82 but median survival was only improved by two weeks. And so based on this study that the FDA did approve or a lot and I've in combination with jump side to be however, given uh the the clinically questionable improvement in survival, this was really never widely used in practice. Yeah. And so we would have to wait until the next decade in 2011 in 2013. Uh for two pivotal studies with multi- Agent chemotherapy where survival rates start to approach one year. And so here you see a pivotal study with full paradox which is for those who don't know, five flurry uracil oxalate, platinum, arena teak and combination of three drugs compared to gem cited being. And what you'll see is that this really was quite unprecedented in the field with a median overall survival of 11.1 months with the triplet regimen compared to 6.8 months. And median progression free survival was also improved. And, you know, not surprisingly, given the triplet chemotherapy, there was a significant increased rate of adverse events with the triplet chemotherapy. However, um when um they looked at degradation of quality of life, this was actually slower in the triplet therapy compared to single agent therapy. Really suggesting that the improvement in symptoms from the cancer outraged that outweigh the increased toxicity of the regimen. But since then, modifications have been undertaken uh to make the regiment more tolerable while maintaining efficacy. And uh the other pivotal multi agent study looking at jump side of being a nab paclitaxel versus jim side of being this study looked at uh over 800 patients who were randomized to the doublet versus the single agent. And you can see that this uh two showed improved overall survival of 8.5 months compared to 6.7 months with an increased response rate of 23% with the doublet compared to 7% with single agent. Yeah. So here you can see a comparison of the different adverse events with the multi agent regiments and what I'll point out is that the full fare knocks regimen compared to genocide are being led to more neutropenia, fatigue, uh neuropathy and gi symptoms. Whereas the jump site of being in that paclitaxel led to an increase in know your apathy and neutropenia. Mhm. I think this is sort of a nice uh slide to show the different um outcomes and also uh populations that were enrolled in both of these studies. Um And what you can see is Uh huh. That um the study uh with Phil Fearon Ox was conducted solely in France. Whereas the impact study was an international study. You'll also note that the performance status of the patients and the impact study. Um they had far fewer very good performance performance status zero patients, 16% as opposed to in the fall Fairy Filthier knock study with 37%. Um They also had an impact study more metastatic disease sites really pointing to a overall sicker population in uh the impact study. Okay, so taking the data and combination, both fulfill an ox and jim side of a nap paclitaxel are accepted. Frontline regimens in the treatment of metastatic pancreatic cancer. So the question, you know clinically is how do we choose for our patients? And this is really based on a variety of factors that we uh look at, including age, their functional status, uh their comorbidities and of course the patient preferences. Okay, So following the approval of these two multi- Agent therapies, there was a small pause until 2015. Um where over the past 5-6 years, the pace of development and approvals of therapy has really picked up. So in 2015, Nana like Lazo Marine Atika and was approved in the second line treatment of pancreas cancer. And this is a novel formulation of arena Tika has shown on the left uh in which encapsulated drug molecules are in a long circulating life zone based nanoparticle and the design is really to allow for more favorable pharma kinetic and bio distribution and when nano liposome ballerina chickens compared to standard or arena he can There's a similar to more exposure to the active metabolite sn 38 at lower doses. And it also allows for prolonged tumor exposure. So here you see the study um of nano liposome amina tika and five F. U. Uh compared to five F. You. And this was in uh advanced pancreatic cancer patients who have progressed on first line jim side of being containing regimen. And it didn't meet its primary endpoint of improved overall survival with 6.1 months for the combination versus 4.2 months. This was really a landmark study as the first FDA approved 2nd line treatment for advanced pancreas cancer. So following approval of nationalized like those normal arenas he can um there was rapid rate of approval of drugs based on precision medicine. And so you know, I think that what I hope you'll take away from this talk is that precision medicine has really significantly altered the way we approach and treat pancreas cancer currently. And so with the advent of next generation sequencing we can now identify very rapidly and affordably genetic alterations and to us and then potentially match them to the ever growing number of targeted agents that are in development. So I think this is a really interesting um retrospective study that looked at over 1000 pancreatic cancer patients who all underwent molecular profiling with next generation sequencing. And of the 1000 patients, nearly 700 had outcome information. And what they found was that a 189 or 28% had actionable findings. And of those, 189 46 received molecular really matched therapies or targeted therapies. And 143 received unmatched therapy. And you can see that those who were matched to therapy had a median overall survival of nearly three years, whereas the unmatched uh had a overall survival of a year and a half. And so this really uh suggests that genomic profiling can be used to identify a sizable portion of the population um for whom you know, precision medicine can make really valuable um impacts for. Yeah. So NGS efforts have consistently shown at least a 25% at least 25% of pancreas cancers have um um highly actionable molecular alterations. And as you see here um the top ones are those that have been proven or have anecdotal clinical data in pancreas cancer in the middle trench are proven or anecdotal evidence in other cancers. And then at the bottom are those with promising pre clinical data. And you know this is all very exciting. But of course we do have to note that any the prevalence of any one of these alterations is very small. So now I'd like to turn your attention to the most recent drug approvals for patients with advanced pancreas cancer, all of which come from identification of a genetically selected population. And these include uh media genic subtypes specifically EMC high tumors. Uh a DNA damage repair um Subtype including Barocco 1 to alter tumors and then rare genetic abnormalities including entropy fusions. Yeah. So the mismatch repair pathway is very important in maintaining DNA replication. Fidelity and our genomic stability. And we know that sells with an abnormally functioning pathway are not able to correct errors during replication. And this causes an inconsistent number of micro satellite nucleotide repeats leading to the instability of the micro satellite lesion regions. Um And this really reflects the condition of genetic hyper mutability. Um And there's about 100 to 1000 fold increase in the mutation rate in these tumors with miss natural paired defects in pancreas cancer. Mismatch repaired deficit. Rmc high tumors are found in about 1% of all pancreatic cancers. And so in early studies looking at immune checkpoint inhibitors such as C. T. L. A four and PD one antibodies, there was minimal to no activity seen in all comers. However, um when um the when tumors with EMC high status were looked at exclusively with treatment uh with Embolism Abbott PD one inhibitor, you see that of the um six patients included in this study with EMC high uh tumors, five of them responded And all of them benefited. In another study. Looking at MSC high tumors, there were 22 patients. So uh you know more than three times the number in the other study. And you can see that there was an 18% overall response rate. Which when compared to the other tumors in the study was the lowest amongst them really. Speaking to the fact that in pancreas cancer we're probably going to need uh additional therapies in combination with uh PD one inhibition for EMC tumors. But nonetheless um based on these data, member Elizabeth was approved um and became the first biomarker based treatment in pancreatic cancer. So it was a very exciting approval. So now turning on to other biomarkers in pancreatic cancer. Um So 17 to 25% of tumors harbor mutations in the DNA damage response and repair genes. And the most notable include A. T. M. Baraka Pal V two and SM 51. And these D. N. A damage response genes can be identified both by germline testing and normal cells as well as in uh sequencing on tumor cells themselves and for somatic mutations. And what has been recognized that uh is that DDR deficiencies are a predictive biomarker to response uh to platinum therapies. So on the left you see uh respected patients who were treated with platinum ferry therapy broken down by whether they had deficient uh DNA damage repaired status versus proficient. And you can see a significant improvement in survival of 3.8 years compared to three years for those patients with deficiency. And a similar survival advantage was seen in the advanced stage 1.5 years 2 2.1 years. So one of the most common DDR deficiencies and pancreas cancer is bracket mutation. And we know that about 5 to 7% of patients with pancreas cancer have journal and Barack a one and two mutations and these mutations are enriched in um certain populations including Ashkenazi, jews, those who have familial pancreas cancer as well as those who have familial breast and ovarian cancer. However, 40% of patients who are germline BRCA mutation do not have any family history. And so as a result, given the higher than previously expected rate of germline alterations in patients with pancreas cancer which is estimated to be about 10%. National guidelines now recommend that any patient who has a confirmed diagnosis of pancreas cancer undergo germline testing in addition. And I'll discuss in more detail guidelines also now recommends dramatic testing for all patients diagnosed with advanced stage pancreas cancer to try to identify uncommon but actionable mutations. Yeah, so in 2000 and 19 another targeted agent was approved elaborate, which is a park inhibitor and it was approved based on this polo study which was an international randomized double blind phase three study which looked at patients with metastatic pancreas cancer with germline BRCA 12 mutations Who had received at least 16 weeks of platinum therapy without progression. and um they had to screen over 3000 patients um to ultimately enroll Uh over 200 patients with germline bracket mutations. So is 7.5 prevalence. And the primary endpoint in the study was progression free survival. And so you see they did meet their progression free survival endpoint. So part inhibitor improved the PFS 7.4 months compared to 3.8 months. However, uh secondary endpoint of overall survival was not met. And when we look at the final overall survival data, there's still no um Difference in median overall survival. But there is a clinically significant improvement in three year overall survival. With those receiving maintenance elaborate surviving uh 34% of them surviving 23 years, whereas only 18% of the patients who received placebo were alive at three years. So so the next key developments in the treatment um a pancreas cancer have come from to agnostic drug approaches. and truck is a gene family that contains 33 members um And they are rare alterations in solid tumors and specifically in progress. You are a current about 1% of pancreatic tumors but are more common in diseases such as infantile fibrous sarcoma or secretary breast cancer. And uh laura Check. Deneb is this highly selective oral administered inhibitor of n trek. And what you can see here is an analysis of three open label trials, all assessing Lara. Check Deneb in the advanced for treating advanced solid tumors with Entrez gene fusion and you can see for all come are all types of tumors with this um Gene Fusion. There was a response rate of 79%. And looking at the pancreas. The cancer population enrolled, There were two patients with pancreatic cancer, one of whom had a partial response with a median duration of 3.5 months. Yeah, similar to lower tractor neV and tractor neves. Also an orally administered and track inhibitor. And you can see um uh analysis of these three studies that the overall response rate was 57%. And there were two patients in this study also with pancreas cancer, one who who had a partial response in another who had tumor shrinkage. So again this is just um showing how somatic mutation profiling can identify these rare but actionable biomarkers and um the predictive of response to FDA approved therapy for pancreas cancer. So now I wanna turn to some of the emerging strategies um uh that we had sign our and elsewhere are exploring. So the microbiome um is a complex communities of trillions of microbes that live on and inside humans. And we know that the combined genetic material from the microbiome far exceeds that of the human genome. Yes, and the majority of the microbiota is found within the Gi tract. But of course there are also microbiota both on internal and external surfaces of the human body. And we know that um these microbes have co evolved to really help regulate health and disease so they can do this by harvesting otherwise inaccessible nutrients in our diets. They can also help with the integrity of mucosal barriers and contributing to the immune system development. Um and what has been recognized is that despite aosis or an imbalance in the microbiota can contribute to the pathogenesis of many diseases. And in particular has been increasingly recognized that the macrobiotic can contribute to carcinogen icis as well as um play a role in response to chemotherapy and immunotherapy. So with the advent of next generation sequencing sequencing, our understanding of the human microbiome has really increased tremendously. And there are a variety of mechanisms that are hypothesized to address how the microbiome influences cancer development, including a direct impact of bacterial toxins as well as modulation of the host and systemic immune response and finally alteration of microbial and host metabolism. And this can happen in both a direct uh fashion or local fashion versus a remote. So until recently the pancreas was thought of as a sterile organ. And um it is now well established that this is not the case at all. And so here you can see on the left a study that looked at over 100 pancreas tumors and analyzed the bacterial DNA about pancreas tumors compared to organ donor pancreas. And you can see that there was a significant increase in bacterial DNA content um in the in the pancreas to us compared to the normal pancreas and in the independent study shown on the right side. A similar finding was found with increase in bacterial DNA in the summer pancreas. So we know that there is now bacteria within the pancreas. But what is it doing there? Um So there is evidence that it's playing a role in angiogenesis. And here you see a comparison of pancreas growth in the slowly progressive Casey model of pancreas angiogenesis. This is on the left and mice with an intake microbiota were compared to those raised in a germ free environment. What you can see is that the germ free mice on the bottom we're protected from disease progression and stromal expansion as compared to those raised with their intact microbiota. And then in another model and more aggressive Ortho topic KPc model you can see that when treated with antibiotics this significantly decreased the size of the U. S. So in addition to accelerating pancreas development, pancreatic cancer development. The microbiome has also been shown to play a role in anti tumor immunity. And so here you see um in a mouse model uh that when uh there uh the mice are treated with antibiotics there's a decrease in milo divisive suppressor cells. And there's an up regulation of T cell infiltration with an increase in cd eight to cd four ratio. And these T cells are Uh increase in activation. And so um there's a th one polarization of CD four T cells. And there's also an acquisition of a CD eight uh side of toxic cd eight T cell phenotype with up regulation of Tibet interferon gamma and TNF alpha. It's also seen in in with microbial relation with antibiotics is an up regulation of PD one expression on T cells as shown up the top left. Mhm. And so um ah Pancreas cancer mice were treated with anti PDF one by itself uh antibiotics by itself for the combination. And you can see that there was a statistically significant uh decrease in tumor size with the combination suggesting that microbial ablation may in fact enable um efficacy of immunotherapy and pancreas cancer. So in addition to animal data, what's the clinical evidence to support the role of the microbiome in pancreas cancer. So this is a really interesting study done by the M. D. Anderson group looking at long term survivors Of pancreas cancer and short-term survivors. And in their cohort median survival for the long-term survivors was 10 years. And that of the short term survivors was a little over 1.5 years. And what they did was looked at the microbiome composition um of of these tumors uh And compared alpha diversities. The number of species by different methodologies between the short term and long term survivors. And you can see that in the long term survivors there was a statistically significant increase in alpha diversity. They then went on to look at the immune composition um within the pancreas is of the long term versus short term survivors. And they saw positive correlations of uh cD three Cd eight and grams in the tissue densities with overall survival. And they also noted That CD eight and g and be tissue density is correlated with microbiome diversity. The group then wanted to ask whether modulating the gut microbiome, be a fecal transplants could affect tumor growth. And so um they looked at a pancreatic cancer mouse model and treated with antibiotics first followed by a fecal microbial transplant. With either stool from short term survivors, long term survivors or healthy controls. And what you can see on the right is those mice that were transplanted with the stool from the long term survivors had a significant reduction books in there tumor size as compared to the short term survivors and healthy controls. They also showed that within the tumor there was up regulation of um uh T cells and active activated T cells in the long term survivors as compared to the short term survivors. And a down regulation of T. Regs and myeloid derived suppressor cells in the long term survivors. This really speaks uh to the fact that, you know, the gut microbiome is able to colonize pancreas tumors and modify its bacterial composition um to modulate immune function and ultimately affect the natural um history and survival of painting pancreas cancer. So it appears that a variety of variables including genetic alterations in the pancreas, environmental factors like smoking um health conditions such as diabetes or gum disease. And uh instrumentation can all contribute to the display aosis um seen. Um and this altered microbiome um as hypothesized to signal through toll like receptor signaling and leading to immune suppression and ultimate um pancreas cancer progression. And so within such a model this really gives us a potential opportunity uh to try to shift the microbiome community to a more favorable one and really tipped the scales to immune activation. Um And so you know, this can be done by a variety of mechanisms including antibiotics, probiotics with either single bacteria or consortium to and of course a fecal microbial transplant. So based on these data, I've designed a clinical trial that's really first of its kind in pancreas cancer. And here you see the schema and this is looking at a respectable pancreas cancer patient to receive upfront chemotherapy and then they will have a new baseline biopsy followed by broad spectrum antibiotics. And um then immune checkpoint inhibition followed by surgical resection and the primary endpoint in sort of this window of opportunity study is to look at changes in the immune composition within the tumor as well as looking at the changes in the microbiome composition both in the tumor and the stool. And so I'm very excited that hopefully the study is going to be opening within the next few months. Um And I'm hopeful that it's gonna shed some light on how manipulating the microbiome may potentially enable efficacy of immunotherapy and really open uh immunotherapy options to the majority of patients which now you know it's not really effective. It's only been shown to be effective in the 1% MSI high population. So the microbiome in addition to its effects on uncle genesis and immune modulation. It also has been shown to play a role in chemotherapy resistance. And so what's shown here is a subcutaneous colon cancer model in which luciferase expressing an equal I were injected injected and selectively detected uh in uh the tumors in the mice. And you can see that those mice um that were treated with antibiotics displayed a marked anti tumor response to genocide of being as compared to the control which showed a rapid progression. And so it is known that the bacterial enzyme cyp two D. And D. Ominous which can metabolize them side of being into its inactive form um is um and so they looked at E. Coli that were engineered devoid of this enzyme. And you can see um that when um ah that you call a failed to induce drug resistance um engineered e coli without deciding the ominous failed to induce drug resistance to john sighting. So really um uh implying that these uh antibiotics can enhance the anti cancer activity of jim's side of being. And so to confirm that the bacteria from human pancreas cancer can mediate them sight of being resistance. They looked at 65 pancreas tumors and um looked at their bacterial uh D. N. A. And they found that in more than half of the uh samples they identified a species belonging to the class gamma protozoa bacteria bacteria. And this bacteria expresses the site of the indie ominous enzyme. So they then cultured uh bacteria from 15 fresh uh tumors, pancreas tumors um with uh to human colon cancer cell lines and found that nearly all of them became fully resistant to jim side of being suggesting that you know pancreas tumors do contain bacteria that can modulate the sensitivity to jump side of IAN and may play a critical role in mediating mediating resistance to this drug that we commonly use for treatment. So to explore the oral microbiome or excuse me to explore the role of the microbiome in pancreas cancer and other gi malignancies. We'll be initiating a observational prospective cohort study um That's looking at comprehensive mx data including the gut and oral by my oral microbiome. Um And we'll be looking at uh advanced events G. I. Cancer patients. Um and um using a novel platform for analysis with stool meta transcriptome mix and the ends of the study are really just um to have a preliminary characterization of the diversity and composition of the G. I. Cancer microbiome and to look at some of the changes in the microbiome as a function of both treatment and disease progression. And you know the hope is that this really is going to serve as the basis for a larger more focus study um indistinct Gi cancers um and and to kind of tease out the relationship to specific treatment efficacy and toxicity. So now shifting gears to different sort of personalized medicine um that of organized as a predictive biomarker. Um you know the currently the personalized strategies that are employed um are really um you know genomic lee based in our serve only to help a minority of our patients. So the thought is that individual tumor response testing on patient direct organ OID can be a better and more widely applicable personalized therapy. And so what are organized there are these miniature three D. Cell culture models that gina typically and Fiona typically um are similar to the original patient tumor and can recapitulate patient responses to chemo therapeutics. And so um we have initiated a study led by my colleagues dr is saying and Hopkins to look at the three D organ OID model and how it may predict response to neo adjuvant therapy and pancreas cancer. And so um you see the schema here on the right. But the primary objective is to look to validate this platform as one that correlates the clinical pathologic response in these patients. And then also to look at whether the organized response to therapy is predictive to patient outcomes. And now turning to chaos which as I discussed at the beginning of the talk is the most commonly mutated gene within pancreas cancer um as you can see at the top right here in the wild type uh ST uh the wrasse protein cycles between uh active GTV GTV bound state and an inactive GDP p balance state. Um and in response to activation of upstream receptor kindness is like a G F r ross becomes bound to GTP. Um and I switched on activating downstream cellular pathways such as ralf neck ERK and PI three kinase in the angiogenic grass. Um these carries mutations lead to impairment of GTP hydraulic Asus um and can also result in an excess of active, excuse me also can accelerate GDP GTP exchange and result in a excessive active GTP pound. Um Kay ross that is kind of switched permanently into its active state. So there are multiple activity mutations that are seen in KRS that are found in various proportions across different cancer types. And this is showing the distribution within pancreas cancer. Um where are the most commonly found keras mutations are G 12 D B and R and direct inhibitors have really been very challenging um to develop in the past due to the shape and structure of the grass protein. However, new approaches, specifically targeting the G 12 CI SEI form are changing the treatment landscape and making would have been thought really to be an undrinkable target, really, really a viable target now. Mhm. So keras, G 12 C mutations are found in about 1% of pancreatic cancer patients. But this subgroup is important to identify given the development of the various G 12 C inhibitors and the way these drugs work is they bind uh covalin tli with the Sistine and lock the protein into an inactive state. And here you see data from two of the KRS G 12 C inhibitors um in pancreatic cancer and so on. The left is so aggressive um which showed up primarily a stable disease in 11 patients. And then on the right, is that aggressive? Which showed a five out of 10 response rate? Um So as seen with other small molecule inhibitors, Kors G 12 C uh inhibition can induce an adaptive resistance um with loss of negative feedback and up regulation of ERK signaling. And so one potential approach to inhibit uh is to inhibit the guanine, guanine exchange factor sauce one um which uh can shift chaos into the GDP bound state and thereby potentially augment the ability for G 12 C inhibitors um uh to to work and and decreased downstream signaling. So pre clinically G two L. C inhibitor plus um uh the Soft one inhibitor have shown to significantly decrease downstream possible ERK signaling compared to either agent alone. Um And this And the Sauce one inhibitor may increase the activity and we're durability of um Uh care SG 12 C inhibitors. Um So based on this data, we are participating in a Phase one study in keras, G 12 C mutated tumors, all tumors including pancreatic cancer. Looking at photographs of the G 12 C inhibitor in combination with a sauce one inhibitor. And be interesting to see to see how these drugs are tolerated. So I think we've really come a long way in our understanding of the biology of pancreas cancer and the resulting treatment including multi agent chemotherapy part inhibition for germline BRCA mutated patients. Give me no therapy in the uh with embolism oB and the MSC high tumors and truck inhibitors for those patients with interest to us uh fusion tumors. And so I think we can you know easily say that the personal personalized approaches here and that no longer can we treat patients with a one size fits all mentality um and Germline and somatic genetic testing or standard of care. So where do we go from here? I think you know, in chemotherapy? Um the ongoing studies are looking at incorporating second line life is normal arena taken into the front line. There are also ongoing studies looking at adding CISplatin into the doublet combination with jim side of the nab paclitaxel. And um there are studies looking at microbiome manipulation and or stratification um in terms of chemotherapy choice uh the DDR pathway is being targeted in a number of ways with combinations uh like elaborate and um uh immune checkpoint inhibitors or anti angiogenic other DDR pathway inhibitors are being tested in the clinic such as we won A. T. M. And check one. Yeah. And that's key developments in our understanding of the immune system progress more immune landscape. Excuse me in pancreas cancer progress. More active agents are anticipated. And so there are some promising areas including uh cd 40 agonist C. X. C. R. Four antagonists, microbiome manipulation and um cellular therapy. And finally um with increased tumor profiling. You know, there is an opportunity for further broadening of the targeted therapy approvals. And so that testing is ongoing and I think, you know, moving more of these personalized approaches into the earlier stages um such as in the peri operative setting or in the maintenance setting is really something important to kind of move the field forward. Yeah. So they're definitely remain challenges that require unraveling. And I've listed here um some of the key areas uh and those include the complex metabolic dis regulation that we see in pancreas cancer. Uh the near Impenetrable dez Malaysia that is preventing a lot of our treatments from accessing the pancreas tumor. Um targeting of chaos is gonna invariably shown new resistance mechanisms to the inhibitors in development. And so that will be something that's going to need to be um unraveled. And then finally um early detection and prevention which honestly deserves it's entirely owned talk. Um And so, you know, I asked at the beginning can we make the impossible possible. And so I really do think that we're on the right track with genetic and transcription profiling um Focus on personalized medicine and more of an investment in basic translational and clinical research. Um And so I really do believe we're on the cups but making huge advancements in this very terrible disease. And so with that I just want to acknowledge my G. I. Medicine surgery and oncology colleagues as well as my laboratory collaborators both here and at N. Y. U. And then the funding support I've received and I thank you for your attention and I'm happy to take questions. Thank you. Dr cohen there are there are some we even moments for questions that's at the end of the hour. Um There's a question in the Travis is there was a study in science a few years ago in mouse and a mouse model showing that decreasing fibrosis made the pancreatic cancer sensitive to chemotherapy. Has there been follow up in unions? Yeah. Yeah. So there there have been, you know, studies like with with highly ironic these uh inhibitors which have not um been successful. Um There are other agents currently um in clinical trials that were awaiting uh you know, readouts from. But as of now, you know, again that's one of the challenging areas is the dense dez Malaysia and how um we can uh kind of reverse that. Is there anything you can comment on about liquid biopsies and they've been used for. Mhm. Yeah. So I mean we're at just the beginning of understanding um liquid biopsies and in fact I didn't actually should have included that. Here we are launching a study looking at sort of the uh response to preoperative therapy. Uh looking at the dynamics of circulating tumor DNA um in response to preoperative therapy. And then, you know, looking at outcomes um in terms of surveillance using this mechanism but it's still being studied and so um it's sort of in its early days, aren't you? Um And then there's a question about any role for your lesson. Eh? Yes, I am not familiar with that. So I don't know the answer. Got it, That's good, good response. Er And then um How about would you take this approach and a 95 year old? And this question came in towards the very end. Yeah, I'm not sure which approach. Um But you know, I guess would I treat a patient with who, you know, it's not all about age as everyone knows right? There's biologic age and there's actual age. So, you know, we kind of have to take things case by case. Um But I'm not entirely sure which approach we're talking about there, imminent logic. She just wrote. Yeah. Uh So certainly in A. M. S. I. High patient one could consider, you know, uh not a patient but the tumor patient with an M. S. I. High tumor. One could consider treating with uh pD one inhibitor inhibitor. It's relatively um you know the adverse events are relatively low and mainly, you know in terms of like rare auto immune side effects. But you know, it depends on what the patient's comorbidities are. Uh huh. Great. Well, thank you, dr cohen for this very comprehensive talk around pancreatic cancer. That was really terrific. So thanks very much. And uh have a nice day, everyone. Thanks for coming to grand rounds. So you also thanks Deirdre.
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