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Siteman Investment Program awards $2.1 million in cancer research grants

Research on pancreatic cancer and multiple myeloma are among the eight projects that will benefit from $2.1 million in new grants announced by Siteman Cancer Center through its Siteman Investment Program. The goal of the grants is to support and accelerate the pace of innovation in cancer research.

The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge and Illumination gala, through the Cancer Frontier Fund at the Foundation for Barnes-Jewish Hospital; Swim Across America – St. Louis; Fashion Footwear Association of New York; National Cancer Institute; and Barnard Trust.

The research projects are described below.

Title: Restoring PDAC Responsiveness to Immunotherapy by Targeting Conventional Dendritic Cells

Principal Investigators: David DeNardo, PhD, and William Hawkins, MD

Goal: To test whether a novel combination therapy in PDAC patients will prime the patient’s immune system to attack cancer cells and drive tumor-protective immunity during and after pancreas cancer surgery

Description: Pancreas cancer is a devastating diagnosis with a five-year survival rate of less than 10 percent. Attempts to employ immunotherapy in pancreas cancer have not achieved significant clinical benefits. This is likely due to the profoundly immune- suppressive environment in which pancreas tumors grow. Our group has found a way to prime the immune system to attack the cancer even in its hostile home environment. We have done so by targeting one immune cell type, called dendritic cells. Dendritic cells act as field generals for the immune system, directing and coordinating attacks on cancer. Unfortunately, patients with pancreatic cancer systemically lack this critical cell type. We have discovered a therapeutic combination that restores dendritic cell numbers both systemically and with pancreas tumors. We have observed in animal models that this strategy results in coordinated immune attacks on cancer cells and in disease control. We now seek to employ this strategy in human pancreatic ductal adenocarcinoma (PDAC) patients by treating them with a combination of FLT3L and CD40-agonists therapeutics. These are the agents that we have shown can drive dendritic cells to coordinate immune attack on the tumor, and our belief is this will drive tumor-protective immunity during and after pancreas cancer surgery.

 

Title: Phase II Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Uproleselan (GMI-1271) for GI

Toxicity Prophylaxis during Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation

Principal Investigator: Geoffrey Uy, MD

Goal: To test if the drug uproleselan can reduce the severity of injury to the gastrointestinal (GI) tract and lessen GI symptoms for multiple myeloma patients following chemotherapy

Description: Injury to the mucosal lining of the GI tract, also known as mucositis, is a major complication of chemotherapy resulting in pain, nausea and diarrhea. Mucositis also places patients at increased risk for infection, malnutrition, prolonged hospital stays and can limit the ability to tolerate further treatment for their cancer. In this study, we are testing if a medicine, uproleselan, can reduce the severity of mucositis and GI symptoms after chemotherapy. Uproleselan blocks a molecule called E-selectin, which is important in how white blood cells travel to the GI tract after injury from chemotherapy. We will conduct the study in patients with multiple myeloma who are receiving high-dose chemotherapy followed by an autologous hematopoietic cell transplant. While autologous transplants are very effective at treating multiple myeloma, the treatment is associated with high rates of severe GI toxicity from mucositis.

  

Title: Gene Dosage Effects and Silent Cancer Mutations in Minor Splicing Factor ZCRB1

Principal Investigator: Sergej Djuranovic, PhD 

Goal: To understand how gene regulation and protein production is altered in cancer cells by dissecting the importance of specific RNA motifs in the ZCRB1 gene, a gene which is known to further control the production of cancer-related genes

Description: Protein production by the ribosome is central to life and disease. Information embedded within DNA is copied into messenger RNA (mRNA), which is subsequently translated into protein. Ribosomes, a complex molecular machine found in all living cells, are the sites of protein translation. Ribosomal stalling and frameshifting are control mechanisms that occur during protein production in cells. The direct consequence of ribosome stalling and frameshifting is lower levels of protein production and production of shorter and non-functional protein forms in cells. Recently, we discovered that the presence of certain RNA motifs (polyA tracks) in mRNA sequences induces ribosomes to stall and misread the encoded information. Abnormal forms and levels of a particular protein may negatively impact health of the cell and therefore lead to cancer. Our goal is to dissect the importance of polyA tracks in the ZCRB1 gene, a gene that further controls production of multiple cancer-related genes. The knowledge that we gain will broaden our understanding of how gene regulation and protein production is altered in cancer.

  

Title: The Role of RAMS11 in Metastatic Colorectal Cancer

Principal investigators: Ryan Fields, MD, and Chris Maher, PhD

Goals: To study how a particular molecule from a newly discovered class of molecules (called lncRNAs) acts to alter normal cell function and promote colorectal cancer metastasis chemotherapy resistance

Description: Colorectal cancer (CRC) is the most common gastrointestinal cancer in the U,S., with approximately 50 percent of patients developing advanced disease. This represents an unmet clinical need to improve the current inadequate treatments. Currently, our limited understanding of the ways in which the original colon tumor spreads throughout the body (also known as metastases) is a critical barrier for improved treatment. We discovered a new class of molecules involved in metastasis called lncRNAs. Based on our preliminary data, we will study a promising lncRNA that acts as a “master regulator” by interacting with specific proteins to alter their normal function, cause tumor spread/metastases and promote chemotherapy resistance. In the longer term we intend to “drug” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this deadly disease.

 

Title: Developing an Academic and Community Practice Collaborative Care Model for Metastatic Breast Cancer Care

Principal investigator: Ashley J. Housten, OTD, MSCI

Goal: To implement and evaluate a coordinated care model for metastatic breast cancer patients in the St. Louis region to improve collaboration between academic and community oncology practices

Description: Meeting the needs of patients with metastatic breast cancer can be challenging due to the multifaceted coordination required to address their complex care. Although national guidelines exist for the treatment of metastatic breast cancer, they do not clearly state the best sequence of treatments; nor do they describe how and when to identify and engage patients in clinical trials. The lack of a clear process for the routine care of patients with metastatic breast cancer may lead to under- and over-use of care and undue patient and system burden. Using an implementation science approach to guide multilevel program adaptation, we propose adapting and evaluating the coordinated care model, Ending Metastatic Breast Cancer for Everyone (EMBRACE), from the Dana-Farber Cancer Institute, to the St. Louis region. This adaptation will enhance collaboration between academic and community oncology practices to improve satisfaction and acceptability among patients and clinicians.

 

Title: Theranostic Approach to Chemo-Resistant Multiple Myeloma through VLA-4 Imaging and Nanotherapeutic Targeting

Principal investigators: Gregory Lanza, MD, PhD, and Monica Shokeen, PhD

Goal: To develop proof-of-concept evidence related to the therapeutic response and effectiveness of a new targeted combination nanotherapy for patients with multiple myeloma

Description: Multiple myeloma is a multifocal bone plasma cell neoplasia that causes systemic organ damage, and is characterized by a recurring and/or progressive course. Over the past two decades, new anti-myeloma therapeutics and bone marrow transplantation after high-dose chemotherapy have improved survival for many patients. However, patients with high-risk mutations can rapidly progress despite treatment, and all of the responders eventually develop relapse, undergoing multiple lines of treatment. Very late antigen-4 (VLA4) is a receptor that is over expressed on multiple myeloma cells, and it helps multiple myeloma cells to adhere to the bone stroma improving their survival and resistance to drugs. The small molecule 64Cu-LLP2A can bind with high affinity to VLA4 on multiple myeloma cells, and allow their imaging by positron emission tomography (PET). 64Cu-LLP2A is able to detect multiple myeloma lesions in small-animal models with high precision, and is currently undergoing safety and efficacy evaluation in patients. Preliminary data suggest that VLA4-targeted therapeutic nanoparticles (20 nm) may be particularly effective for treating chemo-resistant multiple myeloma due the increased VLA4 cell surface levels, selectively delivering anti-myeloma drugs. This project will develop proof-of-concept evidence for two fundamental hypotheses: 1) 64Cu-LLP2A signal intensity is correlated with therapeutic response to VLA-targeted combination nanotherapy, and 2) chemotherapy increases VLA4 levels on residual drug-resistant multiple myeloma cell membranes (R-MMC) that is recognized by 64Cu-LLP2A and predictive of the effectiveness of VLA4-targeted nanotherapy to circumvent chemoresistance. The long-term vision of this program is the use of 64Cu-LLP2A/PET to detect residual drug-resistant multiple myeloma cells (R-MMC) early, triggering specifically targeted “trojan horse” nanoparticle treatments that will use this common mechanism of drug resistance to selectively treat and deplete R-MMC, to delay disease relapse and improve patient survival.

 

Title: Functional Interrogation of JAK2 and ASXL1 Mutations in Myeloproliferative Neoplasms

Principal investigator: Stephen Oh, MD, PhD

Goal: To determine how two of the most common mutations associated to myeloproliferative neoplasms contribute to disease development and identify novel insights that can provide the basis for therapeutic intervention and prevent progression to acute leukemia

Description: Myeloproliferative neoplasms are chronic blood disorders that that can cause severe symptoms and early death. New treatments have become available that help ameliorate symptoms, but they do not reliably slow or halt disease progression. We seek to better understand what drives disease development and progression in myeloproliferative neoplasms, so we can develop better therapies for patients with these diseases. The overall goal of this project is to determine how two of the most common myeloproliferative neoplasm-associated mutations, JAK2 and ASXL1, contribute to disease development. We will utilize innovative approaches to directly study human cells harboring these mutations. The focus of these studies is to identify novel insights that can provide the basis for therapeutic intervention to ameliorate myeloproliferative neoplasm disease features and prevent progression to acute leukemia.

  

Title: The Role of DDR in Normal and Malignant Hematopoietic Cells

Principal investigators: Alessandro Vindigni, PhD; Grant Challen, PhD; Nima Mosammaparast, MD, PhD; and, Luis Batista, PhD

Goal: To understand how certain DNA mutations drive accumulation of cancer-causing blood cells with age, and to develop new methods to eliminate these cells as a way to prevent blood cancers as well as to identify new treatment approaches 

Description: Hematopoietic stem cells (HSCs) reside in the bone marrow and are responsible for the lifelong regeneration of the blood system. But as we age, these cells accumulate genetic mutations which can alter their function. HSCs that acquire genetic mutations in particular genes have a growth advantage and become dominant in the blood system, a phenomenon called clonal hematopoiesis (CH). While the majority of people who have CH will live normal healthy lives, the mutations that predominate in humans with CH are also those which drive blood cancers, including leukemia. Accordingly, people with CH have a much higher lifetime risk of developing blood cancers. Thus, understanding how these specific mutations alter HSC function is important and ultimately may identify ways to prevent these blood cancers from forming. One such characteristic that is different in HSCs with CH mutations is altered response to agents that damage DNA in normal HSCs. Our goal is to define how these common mutations protect DNA in HSCs, allowing them to survive environmental stressors that would kill normal HSCs and expand over time. Ultimately, this work will help to develop methods to eliminate cancer-causing blood cells that accumulate with age as a way to prevent blood cancers and identify new treatment approaches.