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Siteman Investment Program awards $1.7 million in cancer research grants

Washington University School of Medicine

Research on breast, prostate and brain cancers, leukemia, the body’s response to cancer treatment, and support for caregivers of hospice cancer patients are among the projects that will benefit from $1.7 million in new grants announced by Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. The grants are being given through the Siteman Investment Program 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; the Director’s Discovery Fund; and Barnard Trust.

The research projects are described below.

Clinical Trial Award Category

Title: Evaluation of Single Fraction Accelerated Partial Breast Irradiation vs. Five Fraction Accelerated Partial Breast Irradiation for Low-risk Stage 0 and I Breast Carcinoma

Imran Zoberi
Imran Zoberi, MD

Principal Investigator: Imran Zoberi, MD

Goal: To reduce the number of required post-lumpectomy radiation treatments for breast cancer patients by determining whether just one treatment of Accelerated Partial Breast Irradiation is as safe and effective as the five-treatment standard of care

Description: Women with small breast cancers often are treated with a surgery called a lumpectomy. This surgery removes the breast cancer and a small amount of surrounding normal breast tissue. Some of these women also are treated with radiation therapy. This is given after a lumpectomy to lower the chance of the breast cancer coming back. This treatment has been performed since the 1980s and involves X-ray treatments to the entire breast, given once a day for several weeks.

Trials done in the early 2000s on women with small breast cancers have proved that radiation therapy does not need to be given to the entire breast. This type of radiation therapy is called Accelerated Partial Breast Irradiation, or APBI. Later trials have shown that APBI can be given using X-rays for five treatments, which is the current standard of care for APBI at Siteman.

There is another method of APBI that gives a single radiation treatment immediately after a lumpectomy in the operating room. This is called intraoperative APBI. Washington University radiation oncologists at Siteman liked the idea of one radiation treatment but were not comfortable giving this radiation therapy without knowing all the details of an individual patient’s breast cancer. Instead, in 2014, they did a trial of a single APBI treatment given in a regular radiation room a few weeks after surgery in patients whose cancer had been completely removed with spread of cancer to lymph nodes. Fifty women participated in that trial, and there were no troublesome side effects from the treatment.

The current proposed trial continues to study single APBI treatment by testing it against the five-treatment standard of care. The trial is open to breast cancer patients who are postmenopausal and who have small cancers that have not spread to lymph nodes. These patients will either get one or five ABPI radiation treatments. We will check on all participating patients for five years to see if one group does better. Our hope and expectation is that both groups do well. If breast cancer patients could be treated with just one radiation treatment that is safe and effective, it would be great news for this large group of patients.


Pre-R01 Award Category

Title: PKN1 as a Novel Therapeutic Target to Prevent and Treat Graft-versus-Host Disease

Jaebock Choi, PhD, MA

Principal Investigator: Jaebok Choi, PhD, MA

Goal: To determine how a certain protein, PKN1, in a bone marrow donor’s immune cells causes graft-versus-host disease, and how inactivating this protein would allow the healthy immune cells to attack the patient’s leukemia cells but not healthy organs

Description: The most effective treatment for many patients with leukemia or other blood cancers is to administer bone marrow transplants containing immune cells obtained from a healthy donor. Although these cells can effectively kill the patient’s cancerous cells, in about 50% of patients the donor cells begin to attack the patient’s skin, intestines and liver in a phenomenon known as graft-versus-host disease, or GvHD. GvHD can be severely debilitating or even fatal and is the primary obstacle to successful transplantation. We have identified one protein in the donor immune cells that causes GvHD in mice. Pharmacologically inactivating this protein, named protein kinase N1, or PKN1, an enzyme controlling cellular signaling, eliminates GvHD, yet the healthy immune cells can still kill the patient’s leukemia cells. In this proposal, we will determine how this protein causes GvHD. This will have a major impact in the development of new therapeutic strategies to provide an inexpensive, safe and effective way of overcoming the barriers to successful transplantation and will permit the routine use of bone marrow transplantation in patients who may not have suitable donors to improve outcomes.


Title: Transcriptomic Assessment of Anti-Tumor Immunity in Locally Advanced Rectal Cancer

Dr. Ciorba
Matthew Ciorba, MD

Principal Investigators: Matthew Ciorba, MD, (pictured) and Jonathan Mitchem, MD, in a collaboration with the University of Missouri in Columbia

Goal: To identify new personalized therapeutic approaches for rectal cancer that increase cancer-free survival and reduce treatment-related side effects

Description: Rectal cancer affects more than 40,000 people in the U.S. each year. At the time of diagnosis, most of these cancers have spread beyond the wall of the rectum into nearby tissues or to nearby lymph nodes. This spread necessitates a combined approach to treatment, including chemotherapy, radiation and surgery. Despite this aggressive approach, nearly half of patients have their cancer return within five years and, unfortunately, these therapies have significant negative side effects. Therefore, there is an important need to identify new therapeutic approaches for rectal cancer that increase cancer-free survival and reduce treatment related side effects. Researchers at Siteman Cancer Center and Ellis Fischel Cancer Center at the University of Columbia have formed a team to address this need. Ciorba, a gastroenterologist, and Mitchem, a colorectal surgeon, will use state-of-the art techniques for analyzing gene expression within tumors, to identify how immune cells present in a tumor at diagnosis can be used to identify patients most likely to benefit from aggressive therapy. Additionally, this work will look to identify new pathways to target for future rectal cancer therapies. To take the next step in testing the new therapy, the research team will use patient-derived biopsies to build a “living biobank” of cancer and immune cells for use on new targets identified. In summary, using cutting-edge techniques for data acquisition and analysis, along with building a testing platform using human samples, this project will establish a precision medicine pipeline to facilitate identifying new personalized approaches to treating patients with rectal cancer.


Title: Targeting ATR in TP53-mutated AML/MDS

Link Daniel
Daniel Link, MD

Principal Investigator: Daniel Link, MD

Goal: To test the therapeutic activity of drugs targeting the ATR gene in combination with drugs that inhibit DNA replication in TP53-mutated acute myeloid leukemia

Description: Acute myeloid leukemia (AML) with mutations in the TP53 gene represents approximately 10% of cases and carries a dismal prognosis. Indeed, there is no effective treatment and median survival is less than 6 months. Accordingly, there is a pressing unmet clinical need for better therapies for these patients. We have early evidence suggesting that TP53-mutated AML is especially sensitive to drugs that inhibit the ATR gene, especially when combined with drugs that inhibit DNA replication (the process by which DNA makes a copy of itself). Here, we will rigorously test the ability of such drug combinations to kill TP53-mutated AML in the laboratory. Importantly, drugs that inhibit ATR and DNA replication are already being used in the clinic (although not together). Thus, if successful, this research could rapidly lead to a clinical trial of this novel drug combination for patients in this very high-risk group of AML with limited treatment options.


Title: Dissemination of an Evidence-Based Intervention for Caregivers of Hospice Cancer Patients

Debra Oliver
Debra Oliver, MSW, PhD

Principal Investigator: Debra Oliver, MSW, PhD

Goal: To work with state hospice organizations to develop and test an implementation strategy to support a nationwide network of online support groups for caregivers of hospice cancer patients

Description: Cancer patients receive care not only from professional providers but also family members. In fact, most care they receive in the advanced stages are provided by family members who are untrained to provide many of the required tasks. Family caregivers are not only stressed and overburdened, but caregiving also has been found to affect their physical and mental health. Family caregivers have a higher mortality and more anxiety and depression than family members who are not caregivers. We are in the final months of testing the use of online support groups for education and support of caregivers of hospice cancer patients. While the preliminary analysis shows these groups significantly improve caregiver anxiety and depression, hospice agencies have been clear in telling us that it will be difficult for them to facilitate and manage such online groups after our research is complete. This proposal seeks funding to complete preliminary work for a future R01 grant that will define and test an implementation strategy to provide online support groups for all family caregivers of hospice cancer patients across the U.S. We will use input from hospice social workers and state hospice association leaders to develop and test implementation strategies to disseminate our online support groups nationwide by using statewide hospice associations that serve several hospice agencies rather than an individual hospice agency. This direct care is a new role for state hospice associations and must be carefully planned and tested before nationwide implementation and dissemination can be successful in a larger grant.


Title: Chemerin’s Role in the Tumor and Immune Microenvironments in Prostate Cancer

Russell Kent Pachynski Md
Russell Pachynski, MD

Principal Investigator: Russell Pachynski, MD

Goal: To explore how the protein chemerin works to treat prostate cancer that has spread into the bones, and to develop this into a treatment that can be used in the clinic

Description: The body’s immune system is able to control the growth of cancers, and the goal of cancer immune-based therapy, or immunotherapy, is to favorably alter the immune response in order to shrink the cancer. Unfortunately, tumors are able to evade or escape the immune system response through a number of means. We recently discovered that one way in which tumors can escape the immune system is by turning off a protein called chemerin in the tumor. Chemerin normally helps direct immune cells to go into the tumors from the blood. We have found in models of prostate and other cancers, such as breast cancer and melanoma, that if we increase the amount of chemerin in the tumors we can increase the number of immune cells that are able to get into the tumors. This results in significant shrinkage of the cancer. Our proposed studies here will look at using chemerin to treat prostate cancer that has spread into the bones, which is commonly seen in men with prostate cancer. We will test chemerin alone and combine it with some other immunotherapies that can help the immune cells become more active against the cancer cells. We have also developed a new immunotherapy based on chemerin. This immunotherapy can be targeted to any tumor type, though we will initially target prostate cancer, and has the potential to improve immune responses and help shrink tumors anywhere in the body. Increasing the number of immune cells in tumors using this new immunotherapy could potentially improve immune responses in those tumors where there are not many immune cells in the tumors, such as prostate, breast and pancreatic cancers, and this could be used alone or in combination with existing immunotherapies.


Title: A Multi-Modal Single-Cell Approach to Developing Personalized Combinatorial Treatments for Glioblastoma

Allegra Petti, PhD, BA

Principal Investigator: Allegra Petti, PhD, BA

Goal: To identify and isolate the distinct cell populations that comprise individual glioblastoma tumors, test the drug sensitivities of each cell population, and identify effective drug combinations tailored to the unique composition of each tumor

Description: Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is a devastating disease. Treatment for GBM has evolved little in recent decades, probably because this tumor type is notoriously complex. Each GBM tumor is heterogeneous with respect to genetics, tumor cell state and immune microenvironment. In particular, a new technique called single-cell RNA-sequencing (scRNA-seq) has revealed that each GBM is a mixture of different types of tumor cells, each with different biological properties. Consequently, each tumor is essentially multiple diseases, and it will probably be necessary to treat each patient with drug combinations targeted to that individual’s tumor. Although scRNA-seq has enabled us to understand the complexity of GBM, it has not yet helped us treat the disease. This is partly because it is difficult to physically isolate and study the cell types discovered using scRNA-seq. Here, we propose a novel approach to isolating these GBM tumor cell populations, studying their therapeutic vulnerabilities and identifying personalized drug combinations that target multiple cell populations simultaneously. Our approach is based on a new technology called CITE-seq, an extension of scRNA-seq that will enable us to define tumor cell populations and isolate them using a technique called flow sorting. We will test the drug sensitivities of each cell population, then identify combinations of drugs that more effectively eradicate the tumor. Our long-term goal is to adapt this approach to the clinic, so we can readily identify drug combinations for any individual’s tumor. 


Title: Understanding Transcriptional and Epigenetic Regulation of Metastasis and Treatment Response in Head and Neck Cancer

Puram S
Sidharth Puram, MD, PhD

Principal Investigator: Sidharth Puram, MD, PhD

Goal: To identify new therapies for head and neck cancers that may prevent metastasis and avoid mechanisms of treatment resistance

Description: Head and neck tumors are composed of cells that are not all the same but instead have different functions, much like bees in a hive. The diversity of bees makes it hard for a single insecticide to kill the hive; the queen bee may be hiding deep within the hive far away from the insecticide while worker bees may leave the hive altogether. We are interested in identifying new therapies for head and neck cancer that might prevent “worker bee” cells from leaving the hive while dynamically responding to mechanisms of treatment resistance, much like bees in the hive avoid insecticide. In particular, we are interested in improving a new class of drugs called epigenetic therapies by better understanding how these inhibitors work using head and neck cancer models. Our prior data suggests some cancer cells may change their shape and ability to invade, which we call a “transitional” state. We believe that epigenetic inhibitors may control this “transitional” program or direct other pathways we have not yet discovered. By understanding how current epigenetic therapies work, we can design a super-insecticide that may be more effective against all the bees in the hive by improving upon the specificity and reliability of existing inhibitors. Our ultimate goal is to develop new, more dynamic treatments for head and neck cancer that may prevent invasion and metastasis while more robustly avoiding mechanisms of treatment resistance.


Title: Targeting Degradation of the AAA+ ATPase p97/VCP to Improve Cancer Chemotherapy Response

Jieya Shao, PhD

Principal Investigator: Jieya Shao, PhD

Goal: To understand how pSer784-VCP, a DNA repair protein, is naturally degraded in cells, and whether such a process can be manipulated to compromise DNA repair and increase cancer chemotherapy response

Description: Although recent years have seen the development of new cancer therapies targeting specific cancer drivers or boosting patient immunities, chemotherapies continue to be the mainstay treatment for patients with triple-negative breast cancer and other cancers for which no easily targetable cancer drivers are available or no clinical benefits are yet achievable through immunotherapies. In fact, our ability to use chemotherapies to treat cancer has improved significantly over the past several years, owing to the development of new drugs with better safety profiles that are more toxic to the tumor cells than the healthy cells. This is best exemplified by the PARP inhibitors, which have received FDA approval to treat multiple cancer types such as breast, ovarian and pancreatic cancer. PARP inhibitors work by causing DNA damage because PARP is a highly important DNA repair protein. In certain tumor cells, such as those harboring BRCA1/2 mutations, DNA repair machineries are defective. Consequently, they are more prone to death when PARP is inhibited compared to healthy cells whose DNA repair machineries are intact. Although PARP inhibitors were originally approved to treat BRCA1/2-mutant tumors, we now know they also are effective for tumors without BRCA1/2 mutations but that are harboring other DNA repair defects. Identifying such DNA repair defects, or findings ways to induce them, can broaden the utility of PARP inhibitors and expand their clinical benefits to more cancer patients. In this study, we focus on a highly important DNA repair protein named pSer784-VCP that drives cellular resistance to different chemotherapy agents including PARP inhibitors based on our recent clinical and experimental investigations. The goal of this study is to understand how pSer784-VCP is naturally degraded in cells and whether such a process can be manipulated to compromise DNA repair and increase cancer chemotherapy response.