Thank you. I'd like to start by thanking the organizers of this session for inviting me to present. And basically, I think it's a very important session, the NIH corner. And I think between the NCI, NIDDK, NIAID, and NIAAA, that we provide a lot of funding to researchers in the liver field. So I think this is a very important session. And again, I thank you for the invitation. Now I'll be talking about hepatocellular carcinoma, biomarkers, and early detection and the NCI programs. I have no disclosures and no conflict of interest. This slide here shows the current AASLD screening guidelines for liver cancer. Basically, they look at high-risk groups such as cirrhosis and patients with HBV infection and without cirrhosis. The screening interval is every six months. The imaging modality is ultrasound. Regarding biomarkers, the only one really is AFP and is plus or minus AFP at the discretion of the physician. So what are some of the challenges? Currently biomarkers lack sensitivity and specificity. Validation and verification studies that combine biomarkers, clinical parameters, and or imaging modalities are needed to improve surveillance and early detection for liver cancer. Access to high-risk patients such as cirrhotic patients with viral or non-viral etiologies. And as we're seeing, many of the viral etiologies are decreasing and the population is being diagnosed with more non-viral such as NAPLD or NASH. And there's also alcoholic liver disease. Translation of patients into high-risk groups for progression to HCC. If we can identify, for example, cirrhotics that remain stable versus those that progress. So stratification is important. And also the burden of HCC is higher in minority populations. This also needs to be addressed. To address some of these concerns, the NCI had released an RFA in 2017 for translational liver cancer consortium. And this established a consortium to advance translational research that is focused on the early detection of liver cancer. There were three major areas of focus. The first being improving surveillance for liver cancer in patients with cirrhosis, increasing the detectability of liver cancers at early stages, as well as approaches to better stratify patients with cirrhosis who are at risk. For this initiative, there were a data management and coordinating center that was funded. And there were five clinical centers that were funded. I have them all listed here. And they addressed risk stratification, early detection, surveillance, as well as biomarkers and screening in patients with cirrhosis. So they addressed those three major areas of the initiative. In addition to this funding that we had, the NCI has resources available for the study of biomarkers. We have reference sets for biomarker validation and verification. One reference set we have is a case control, cases being HCC, controls being cirrhotics. And there is serum, plasma, and DNA available in this reference set. There are approximately 400 cases, and over 200 are early stage hepatocellular carcinoma. The controls are over 400 patients with cirrhosis. And these are patients who had no tumor with at least a six-month follow-up. Now this reference set was completed in 2009, so it was over 10 years ago. But this reference set was used to test the performance of DCP, AFP, and AFPL-3, three potential markers. And a publication came out of this in Gastro in 2019, rather. In addition, the NCI is developing a longitudinal cohort for early detection, the Hepatocellular Early Detection Study, or HEDS study. This is a prospective longitudinal study. The goal is to enroll patients. We have about 1,500 patients enrolled, the majority of which have cirrhosis. There are 71 that have developed HCC in this cohort. And ultrasound, as well as blood, is being collected every six months. Now the goals of this study are to determine the performance of biomarkers and ultrasound for early detection of HCC, to determine the cost-effectiveness of a surveillance strategy, to determine the prognosis of patients with HCC, and very importantly, to develop a well-characterized reference sample set for validation of future biomarkers. So this reference set will be available for validation and verification of biomarkers. And this slide just shows the longitudinal cohort that we have. At time of diagnosis, we have 71 samples available from those 71 patients. And then at six months, 12 months, and 18 months, we also have samples available from these patients who developed HCC. And this will become important in studying the early detection of HCC in these populations. And we detect at six months, 12 months, 18 months prior to the diagnosis. So these NCI resources, this specimen reference sets, are available. If you Google EDRN, you will find the Early Detection Research Network website. If then you go to, here we go, Google EDRN, then you go to Resources, and under Resources, if you look under Reference, Specimen Reference Sets, currently, right now, you will see the EDRN Case Control Reference Set that's available for validation and verification of biomarkers. This is the full website link, but again, if you Google EDRN, and then go to Resources, and Specimen Reference Sets, you will find this information. So in addition to the initiative we had, and then the resources that are available, the NCI recently had a workshop on liver cancer, the Fibrosis to Cancer Workshop in April 2019. And fibrosis really cuts across the mission of several NIH institutes and centers. And we had also asked the NIDDK to help us develop the program for this workshop. And the purpose of the workshop was really to understand the mechanisms and epidemiology of viral and non-viral etiologies for liver fibrosis and the progression of fibrosis to liver cancer. The sessions included basic science, epidemiology, early detection, as well as translational research and clinical trials. And a white paper should come out of this workshop in the near future. So finally, I would like to end by discussing some potential funding opportunities. These are not liver-specific, but you can apply for these grants, and they would be relative to the research that you're doing in liver. And I have a list of those on a flyer that's up here at the front. So if you want to pick that up as well after the session, you're welcome to do that. So some of the funding opportunities we have are, for example, in imaging, biomarkers, and digital pathomics. And the goal of that is to integrate these strategies for improving the current approaches for early detection of cancer. And liver cancer is included in that. Another PAR is the integration of imaging and fluid-based tumor monitoring in cancer therapy. And the goal of that is to use imaging as well as fluid-based tumor monitoring or liquid biopsies assays during cancer therapy in patients to determine the optimal use of those modalities in the characterization of therapeutic responses or the emergence of resistance. There is a provocative questions in cancer dealing with HIV infection. And what they're looking for is understanding the risks, development, and progression, and diagnosis and treatment of malignancies in individuals with underlying HIV infections. Viral infections such as hepatitis are common in patients who also are coinfected with HIV. So this is another potential opportunity for funding. Another PAR is cancer prevention and control clinical trials program. And this is to support clinical trials that have the potential to reduce the burden of cancer through improvements in early detection, prevention, healthcare delivery, quality of life, survivorship related to cancer. Another PAR is in basic research in cancer health disparities. And as I mentioned to you in an earlier slide, the NCI is interested in the cancer burden in minority populations for HCC. And this PAR encourages grant applications for investigators interested in conducting basic and mechanistic research in the biological and genetic causes of cancer health disparities. Another PAR is related to the NCI early phase clinical trials for cancer treatment and diagnosis. And these focus on phase zero, one, and two trials that are focused on cancer targeted diagnostic and therapeutic interventions. And finally, I just want to list two future opportunities. One was a PAR that was looking at exosome derived analytes for cancer detection. This PAR expired, but it will be reissued in 2020. And the goal of that is to isolate and characterize exosomes for the discovery of predictive biomarkers for risk assessment, detection, diagnosis, and prognosis of cancer. And in addition, there will be a funding announcement related to co-infections and cancer. So this is basically all I have. I want to thank you for your attention. Thank you very much. So you actually have a couple minutes. So I think, you know, since the end is really a roundtable to try to talk about cross-institute collaboration, we have, you know, about five minutes or so for questions specific to the NCI if anyone has them. Please just introduce yourself. Yeah. So this is a very nice talk. I wanted to know, so you have a lot of specimens. So we are the basic scientists. How can we benefit for these resources and the specific biopsy? So you already have mentioned that here. Can we get some of the specimen from NCI? Yeah. We do not have tissues. We don't have biopsies, but we do have blood samples that are available. And if you go to that website, EDRN, there will be some information on how to request access to those reference sets. Thank you. Any other questions? So I have one question, which is that in terms of, you know, you have a lot of different announcements that are really cross-cutting. You're looking at imaging, you're looking at the whole, you know, liquid biopsy, all kinds of actually fairly cutting-edge stuff, which can take us all the way from prevention to early detection to advancing therapies. So when a person is thinking about applying and is trying to navigate which would be sort of the best announcement for them, do you welcome calls from investigators who are interested? And how would you recommend they approach the NCI to discuss a potential idea? That's a very good question. What I would recommend that the investigators do is to look at the announcements. And in the announcements themselves, at the bottom of the announcement, basically, there's a list of the program directors or officers that are involved in that initiative. And if your research is comparable to what the research is in the PAR, identified in the PAR, I would contact the program officer and talk to them about your research and what you're planning on submitting. And they could give you advice on the submission process. And they could tell you if your research is responsive to that particular initiative, the funding announcement, or they could direct you in a different avenue and direct you to the proper initiative for your research. But I definitely would contact the program officer for that and work with them. Great. I think for junior investigators, it's really important not to be anonymous. You know, the program officers are there to help you, and so I think the earlier you get in touch and the more you seek their advice, the better your proposal will ultimately be. So don't be a stranger. I know it's hard to kind of get out there and network, but that's really what you need to do. Yeah. One thing I did not touch upon was training grants. The NCI has a number of training grants, and we have a training grant program for pre-docs, post-docs, for clinicians. So there is a lot of information as well available on the NIH website for training grants. And I would also encourage you to look into that if you're in that area, if you're a pre-doc, post-doc, or you're a resident and you're looking for training grants. Yeah. Just a brief question. For researchers who work in companies, is the research that they perform eligible for this kind of funding, or do they need to work with medical or an academic in order to apply? We've had, at the NCI, companies work with us and our investigators collaborate with them. We've also, I'm aware of some funding that has gone to industry as well. So again, it depends on the initiative and what is, you know, what they list there as to potential investigators that can apply for the initiative. Thank you very much.

NIH session

liver cancer research funding

early detection

biomarker validation

high-risk groups