Defining Hepatocellular Carcinoma Subtypes and Treatment Responses in Patient-Derived Tumorgrafts

Principal Investigator: ZHU, HAO
Program: PRCRP
Proposal Number: CA150245
Award Number: W81XWH-16-1-0154
Funding Mechanism: Translational Team Science Award
Partnering Awards: CA150245P1, CA150245P2, CA150245P3, CA150245P4
Award Amount: $405,797.00


Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related death in the United States and is projected to become the third leading cause of cancer death by 2031. HCC is a particular problem for military populations, who have high rates of liver disease from hepatitis C infection, obesity, and alcohol abuse -- all recognized risk factors for HCC. Over four in five patients with HCC are found at non-early stages, when cure is not possible and median survival is less than 1 year. Lack of effective treatments is largely due to a lack of knowledge about the underlying behavior, subtypes, and genetic vulnerabilities of HCC.

HCC is poorly understood because HCC diagnosis does not require tissue biopsy. Investigators usually only study early-stage cancer from favorable prognosis patients because HCC tissues are only obtained if the cancer can be surgically resected. This situation has biased our understanding of the molecular genetics of this disease and is a major barrier to progress in HCC therapy. We strongly believe studying the biology of intermediate and advanced HCC cases should be a major priority. There are clearly distinct phenotypic subtypes of HCC that have different clinical outcomes, but there is little understanding of the basis of these differences. In addition, advanced cancers may have different responses to available and experimental therapies.

HCCs should not only be studied descriptively but also with approaches that interrogate "living" cancers. To increase understanding of this disease, we aim to analyze and functionalize HCC tumors with a large collection of patient-derived xenograft (PDX) models, in which human liver cancers are implanted, grown, and studied in mice. We have begun and will continue to develop an extensive PDX cohort of early and non-early stage HCCs that captures the clinical and genetic diversity of HCC patients in the United States. We have already implanted 25 human tumors into mice and plan to implant 100-150 tumors with funding from this grant, generating at total of ~30 viable PDX models. This "mouse hospital" will allow us to examine differences within a large spectrum of human HCCs and allow us to analyze established and experimental therapies in a precise and efficient manner.

First, we will determine if early and later stage cancers are biologically different. This is a basic question that remains unanswered. Advanced cases are the most challenging clinically, and we know the least about the genetics and biology of these cancers. Identifying differences in how these cancers behave in mice will allow us to ask what genes are different in these cancers compared to early-stage HCC. We can use this information for prognosis. It is also possible some genetic differences could be amenable to specific molecular therapies.

These mice harboring human HCC will allow us to test therapies targeted to important growth pathways in HCC. Our group has expertise on a set of genes in a pathway call the MYC/LIN28B/LET-7 network. It is one of the most commonly activated pathways in HCC, but it has been difficult to design drugs against these genes. To address this limitation, we will exploit our expertise in delivering small RNA molecules that can inhibit any gene of interest. We will determine if and why a subset of HCCs are susceptible to this experimental therapy against the MYC/LIN28B/LET-7 network.

One of the dreams of modern cancer therapy is personalized therapy, i.e., "precision medicine." We will use mice bearing human cancers to tell us which ones are treatable with available therapies. This might provide clinicians information about who to treat with which drugs. In this part of the project, we will define classes that respond and do not respond to available systemic therapies. Our hope is that we can then identify clinical tests that will allow clinicians to predict tumor responsiveness.

Overall, we will interrogate HCCs that are the most clinically challenging and poorly understood and define mechanisms for treatment response to currently available and experimental therapeutics. We believe we can answer these basic but important questions within the timeframe of this grant, providing data to potentially change clinical practice within the next decade. Our hope is that our study will impact the HCC population, which would include active duty Service members, their families, and other military beneficiaries.