Since 2015, the Foundation has awarded more than $1.9 million in funding for innovative, high-quality research.
SALT LAKE CITY, UTAH, USA, August 6, 2019 — The Cholangiocarcinoma Foundation (CCF), a nonprofit organization funding novel research for bile duct cancer, has awarded the 5th cycle of its Research Fellowship Program. CCF is pleased to support 7 projects for a total of $365,000 in its largest funding cycle to date.
Since 2015, the Foundation has awarded more than $1.9 million in funding for innovative, high-quality research. In accordance with the Foundation’s Research Philosophy, CCF supports promising projects that are less likely to get traditional funding. Open-access research that catalyzes collaboration and focuses on finding a cure is a core value of the program.
“Through these studies, CCF’s Research Fellowship Program aims to gain insights and achieve significant milestones into the research of cholangiocarcinoma,” said Donna Mayer, Executive Director of the Cholangiocarcinoma Foundation. “We are proud to honor and support these remarkable scientists and researchers as they carry on the legacies of those for whom the grants are named.”
(click each title below for a description of the project)
Immunosuppressive Myeloid Cells Facilitate Tumor Progression in cholangiocarcinoma
Supported by the Daniel Fuquay family in honor of Andrea Marie Fuquay
Researcher: Emilien Loueuillard PhD, Mayo Clinic
“This proposal uses unique animal models of cancer to examine how the immune cells respond to bile duct cancer. The goal of our research is to understand how a type of immune cells in the liver, “termed myeloid derived suppressor cell” induces resistance to treatment against bile duct cancer, and facilitates the progression of this cancer. This information will help identify approaches to inhibit these cells, and provide a treatment strategy for this devastating human malignancy.”
Targeting FGFR2 Signaling in Cholangiocarcinoma
Supported by Jason Scott & family in memory of Andrea Scott
Researcher: Saireudee Chaturantabut PhD, Broad Institute of MIT & Harvard
“FGFR2 gene mutations occur frequently in cholangiocarcinoma (CCA) causing overactivation of a critical growth promoting pathway. This finding has led to the successful testing of new drugs targeting FGFR in preclinical and clinical trials. Nevertheless, studies have found drug resistance and adverse effects in patients treated with FGFR inhibitors suggesting that drug inhibitors alone may not be sufficient to cure CCA patients. A better understanding of FGFR2 in CCA biology and alternative therapeutic approaches are therefore critical and are the focus of this proposal. Here, we propose to explore antibody-based treatment strategies that we believe will lead to higher efficacy and lower toxicity, and the ability to overcome resistance. We will test these antibodies in CCA cell lines as well as in CCA animal models. We will further utilize novel technologies to engineer and improve current antibodies such that they may have enhanced therapeutic impact in ICC patients.”
B7-H3 specific CAR T Cell Combinatorial Immunotherapy for ICC
Supported by Barbara Dupont, family & friends in memory of Jacques Dupont
Researcher: Theodorous Michelakos MD, MGH
“The number of patients diagnosed with intrahepatic cholangiocarcinoma (ICC), the cancer of the bile ducts inside the liver, has been rising. Treatment options, however, remain limited. To address this need we developed a novel immunotherapeutic strategy. We genetically manipulate T lymphocytes to recognize and destroy ICC cells. These T cells use a chimeric antigen receptor (CAR) to recognize the tumor-specific antigen B7-H3. We also use techniques to counteract mechanisms used by tumor cells to evade T cell destruction. We have shown that CAR T cells are effective in vitro, but only partially destroy human ICC tumors grafted in mice. We hypothesized that this is caused by the low number of CAR T cells reaching the ICC tumors. Thus, we will inject our CAR T cells directly into the vein draining to the mouse liver. The results will contribute to design CAR T cell-based clinical trials for ICC patients.”
Investigating YAP inhibition as a novel treatment for Intrahepatic cholangiocarcinoma
Supported by Brad & Geri Clements in memory of Mark R. Clements
Researcher: Jacquelyn Russell PhD, Boston Children’s Hospital
“Intrahepatic cholangiocarcinoma (iCC) is a rare and deadly liver cancer. The only current treatments are surgery or chemotherapy, but even with treatment only a minority of patients survive. Therefore, better treatments are desperately needed, and the best way to develop new therapies is to understand how iCC grows and spreads. One hallmark of iCC is that it recruits surrounding healthy cells, known as the tumor reactive stroma (TRS), to help promote its survival. We have identified a gene, YAP, which is abnormally highly expressed in both iCC cells and the TRS. Thus, we believe YAP to be important for iCC growth and survival. We can grow iCC in mice such that the cancer is very similar to human iCC, and we will test if removal of YAP from iCC or the TRS reduces iCC growth in the mice. Additionally, we have developed a drug which specifically inhibits YAP, and we will test if this drug successfully treats mice with iCC. This work could develop the basis for a new treatment for iCC.”
Understanding DKK1/GRP78 interactions and the implications for the tumour microenvironment in cholangiocarcinoma
Supported by Janice (current patient) and Dean Meyer – in honor of her mother who also died from CCA.
Researcher: Edward Jarman PhD. University of Edinburgh
“Dickkopf-1 (DKK1) is a protein which downregulates Wnt signalling, a cellular pathway which promotes growth in numerous types of cancer. Despite this, DKK1 is frequently seen at higher levels in CCA and is associated with more aggressive disease. This suggests that DKK1 may be acting in novel ways to promote tumour growth. Our previous work has sought to understand these novel mechanisms by identifying proteins which associate with DKK1. This work has highlighted GRP78 a protein which ensures other proteins inside the cell are correctly folded. However, GRP78 has also been shown to regulate immune cell activity when it is secreted from cells. As well as promoting cholangiocarcinoma growth, we see that DKK1 leads to changes in immune cell abundance within the tumour, dampening the immune response and facilitating tumour progression. We now hope to understand whether DKK1’s interaction with GRP78 promotes tumour growth, perhaps through its extracellular role as an immune modulator. ”
Gut microbiome-dependent accumulation of myeloid cells promotes intrahepatic cholangiocarcinoma
Supported by CCF in memory of Marion U. Schwartz
Researcher: Qianfei Zhang MD, NCI/NIH
“Cancer of the bile ducts within the liver, or intrahepatic cholangiocarcinoma (ICC), is a rare but very aggressive malignancy with no effective treatment options. Gaining insight into the pathologic mechanisms of ICC is crucial to developing novel therapies. Livers of patients with ICC have increased myeloid cells, an immune cell that can suppress the immune system and promote cancer. Little is known about why these cells accumulate there. Several disease states can cause bacteria normally confined to the intestine, known as the gut microbiome, to travel to the liver[4, 5]. There, bacteria can interact with liver cells resulting in production of substances that can potentially recruit myeloid cells to the liver. The relationship between increased bacteria and increased myeloid cells in the liver has not been carefully examined. We hypothesize that presence of gut microbiome in the liver and the subsequent increase in myeloid cells contribute to promoting ICC.”
Deciphering the role of the IDH mutant in the tumor immune microenvironment of cholangiocarcinoma
Supported by Lorraine Twohill in honor of the collaboration between AMMF, Cholangiocarcinoma Foundation, Target Cancer, and The BiliProject
Researcher: Meng-Ju Wu PhD, MGH
“Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are common in patients with intrahepatic cholangiocarcinoma (ICC). While drugs that block the function of mutant IDH show some promise in slowing tumor growth in ICC patients, the tumors rarely shrink and typically begin to re-growing in less than a year. Little is known about how the tumor cells respond to IDH inhibiting drug. This information is important in developing ways to treat these tumors more effectively. Our proposal is based on our findings indicating that IDH inhibiting drugs change both the properties of the tumor cells and their interactions with the immune system. We will examine these interactions in depth and develop approaches that both more effectively block the growth of tumor cells and increase the ability of the immune system to kill the tumor.”
"The Fellowship Program supports research that opens new pathways for diagnosis and drug discovery thereby accelerating a path to a cure.”
— Stacie Lindsey, CCF Founder and President
Cholangiocarcinoma, a highly lethal cancer with poor prognosis, arises from the bile ducts in the liver. It is often diagnosed at advanced stages when treatment is only minimally effective, emphasizing the imminent need for novel therapies. There are no effective strategies for prevention, early diagnosis or long-term treatment, indicating a significant unmet medical need.
Although considered rare, with 12,000+ cases a year being diagnosed in the US, cholangiocarcinoma is the second most common primary liver cancer in the world. Both incidence and mortality are increasing thus research into this deadly disease is urgently needed.