Rhabdomyosarcoma is the most common soft tissue tumor in children. This cancer seems to be related to muscle cells that have not been able to mature normally. This project is investigating the manipulation certain proteins called polycomb proteins. The main goal is to determine if polycomb proteins change the production of other genes that are vital to normal cellular maturation in rhabdomyosarcoma. the hope is to define polycomb proteins as regulators of muscle development and use this information to produce new and targeted treatments for this disease.
The research supported in this proposal will impact patients with ovarian cancer. Ovarian cancer is the most common cause of gynecologic cancer death. Noninvasive imaging is critical for detecting disease and monitoring response to treatment. However, current methods are inadequate and better approaches are urgently needed. Our concept is that the protein cyclooxygenase-1 (COX-1), which is expressed at high amounts in ovarian cancer, can be used to detect and monitor the spread of disease and response to treatment. We will test a first-of-its-kind COX-1 targeted PET molecule in mouse models of ovarian cancer. Our study paves the way to clinical trials of a much-needed new imaging technique to benefit women diagnosed with ovarian cancer.
Funded by UNDEFEATED in honor of Chicago Blackhawks and Darlene Shaw
The experimental therapeutic PAC-1, when combined with FDA-approved drugs for metastatic breast cancer, has been found to give a highly synergistic effect on the killing of the breast cancer cells. Given that PAC-1 is already being evaluated in a Phase 1 trial in cancer patients (NCT02355535), these results suggest future combination trials for the treatment of metastatic breast cancer patients.
Standard treatment for advanced bladder cancer is platinum-based chemotherapy. Unfortunately, this kind of treatment fails in most patients, and in some, it causes life-threatening heart problems. Today, doctors have no way to figure out who would benefit from platinum-based chemotherapy. Our team of researchers from Memorial Sloan Kettering Cancer Center (MSK) thinks that there are genetic reasons why this kind of chemotherapy works for some patients and not others. Pharmacogenetics is the study of how someone’s genetic make-up influences the way they respond to a drug. The goal of our research is to conduct the most comprehensive pharmacogenetic study to date to identify genetic reasons why some patients respond to chemotherapy and some experience lethal heart problems. The generous funding from the V Foundation will allow us to study the DNA of 500 advanced bladder cancer patients from MSKCC who received platinum-based chemotherapy and were then monitored for treatment response and heart problems. We will use a new genetic tool called the OncoArray to measure over 500,000 common genetic differences in those who respond to chemotherapy and those who do not. In addition, we will perform genetic sequencing to investigate rare genetic differences that may be important. Our study has the potential to enable doctors to tailor treatment to the individual patient in order to deliver the best bladder cancer care possible.
One of the most promising approaches for patients with advanced Ewing sarcoma is the use of therapies directed against the insulin-like growth factor-1 receptor (IGF-1R). Preclinical studies provide strong biologic rationale for targeting the IGF-1R pathway in Ewing sarcoma. Early clinical studies of monoclonal antibodies directed against IGF-1R have demonstrated that patients with relapsed Ewing sarcoma have one of the highest response rates to this class of agents. However, only a minority of patients with relapsed Ewing sarcoma responds to IGF-1R inhibition, though often with dramatic clinical responses.
Based on these promising results, the clinical development of IGF-1R inhibitors for patients with Ewing sarcoma is a high priority. The Children’s Oncology Group (COG) is soon to activate a randomized phase II trial for patients with newly diagnosed metastatic Ewing sarcoma to compare standard multiagent chemotherapy to this same chemotherapy with the addition of an anti-IGF-1R monoclonal antibody. I will chair this important clinical trial that has the potential to transform the care of patients with metastatic Ewing sarcoma.
A major component of this trial will be an evaluation of potential predictors of patients with metastatic Ewing sarcoma who are most likely to benefit from IGF-1R inhibition. Identification of these predictors is absolutely critical since data from patients with relapsed Ewing sarcoma suggest that that only a subset of patients will respond to this therapy. This trial provides an ideal and unique opportunity to investigate potential predictive markers of response to IGF-1R inhibition in this disease, both because it is a randomized trial and because it will be the first large-scale evaluation of IGF-1R inhibition in patients with newly diagnosed Ewing sarcoma.
All 126 patients enrolled to the trial will participate in the correlative studies. By evaluating these potential markers in patients treated with and without the IGF-1R inhibitor, we will be able to distinguish prognostic markers from markers that are predictive of response to this targeted therapy.
We will assess several promising markers in this trial, including:
Tissue markers of IGF-1R expression and IGF-1R pathway activation;
Expression of IGF-1R on bone marrow tumor cells at diagnosis and over time in response to IGF-1R inhibition;
Serum markers of the IGF-1R pathway at diagnosis and over time in response to IGF-1R inhibition, including IGF-1, IGF-2, IGFBP3, and growth hormone; and
The COG has funds to conduct this trial, but does not have funds to support the critical embedded correlative biology studies embedded within this trial. Therefore, we are seeking funds to support processing and analysis of samples obtained. Some of these funds will be used directly at UCSF as the evaluation of bone marrow tumor cells is performed at UCSF using only fresh samples. Additional funds would be used by the COG Biopathology Center at Nationwide Children’s Hospital in Columbus, Ohio to support the processing of samples into serum and DNA for testing.
Recently, researchers in the program have discovered a synthetically accessible class of molecules that appear to increase the effects of novel anticancer drugs by several orders of magnitude. The overarching goal is to reduce the working concentrations of ALL anti-cancer drugs in order to mitigate serious side effects. Here, we propose to develop and screen our new molecules with both novel and existing chemotherapeutics against a variety of cancer cell lines in order to define the optimum combination treatment. Also we are working on tumor formation. The life and death of cells must be balanced if tissue homeostasis is to be maintained-there should neither be too much growth nor too little death. Normal cells accommodate this balance by invoking intrinsic programmed cell death, referred to as apoptosis. Apoptosis is triggered via three signaling pathways. If apoptosis does not occur correctly and cells do not die, then malignant tumors form. It is no surprise therefore that countless cancer therapeutics are being developed to control apoptosis. It is known that all three apoptosis signaling pathways route through a protein known as caspase-3. If caspase-3 fails to function, then cell death does not happen correctly and cancer occurs. It is known that a calcium-binding protein known as calbindin-D28K binds to caspase-3 and stops it functioning. If we can stop calbindin-D28K from interfering with caspase-3, apoptosis would occur normally and the risk of cancer developing would be significantly reduced. Consequently calbindin-D28K is a particularly powerful target for anticancer drug development.
Working outside the regular hours of 7am to 6pm, or shift work, has become a critical component of our 24-hour society. With approximately 18% of workers in the US engaged in shift work, the possibility that working at night causes cancer is an important public health issue. While increased cancer risks have been observed among shift workers, the specific factors responsible for the increased risks remain unknown. Identifying these factors is crucial to the development of strategies to prevent cancer among shift workers. Sleep disruption is thought to be a likely causal factor, but little research has been done, and studies thus far have relied on crude measures of sleep disruption. By looking at DNA damage among shift workers and using detailed measures of sleep quality, our study will, for the first time, closely examine the cancer causing role of sleep disruption among shift workers. Though sleep disruption occurs commonly among shift workers, it is not unique to them, so findings from this study will be broadly useful to the protection of health and well-being across the general population.
Funded in partnership with Miami Dolphins Foundation
Having an unhealthy weight increases one’s chance of getting cancer. It also increases the chance of dying in people who already have cancer. Keeping a healthy weight is important, especially for people from Hispanic and non-Hispanic black families who have a high chance of having an unhealthy weight. A program that helps cancer survivors lead their children and grandchildren in keeping a healthy weight may help them make their own health better and may also make their children’s and grandchildren’s health better. If the program uses smartphones and tablets, it may help connect family members who are different ages. The goal of this project is to develop and test a program that uses the Internet and mobile devices to help Hispanic and/or non-Hispanic black female cancer survivors lead their families in keeping a healthy weight. The first part of the project will develop the program by getting feedback from Hispanic and non-Hispanic black female cancer survivors. The second part of the project will test the program to determine if it is possible, well-liked, and shows improvements on the weight, physical activity, and diet of cancer survivors, their children, and grandchildren.
Inhibitors of the poly(ADP-ribose) polymerase enzymes (PARPi) represent a significant advance in ovarian cancer treatment, particularly in those with inherited BRCA1 and BRCA2 mutations. These drugs are taken by mouth, are effective, and generally have fewer side effects than chemotherapy. However, responses to PARPi are generally limited and cancers develop treatment resistance. Inhibition of the ATR kinase offer a promising solution to this problem. Inhibitors of ATR (ATRi) and PARP have distinct and complementary effects. Data from our group shows that the PARPi-ATRi combination causes complete tumor regression in BRCA2-associated ovarian cancer animal models, an effect that is superior to that observed with PARPi alone. Based on these data, we plan a clinical trial of the PARPi, olaparib with an ATR inhibitor in patients with ovarian cancer. With support from the V Foundation, we have set out to further improve this therapeutic strategy. First, we will study tumor tissue from patients enrolled on the clinical trial to identify markers that predict if the treatment will be effective. Furthermore, we will use tumor tissue from patients to create animal models and use these animal models to test ATR inhibitor combinations with different PARP inhibitors, in addition to olaparib. We will determine which PARPi is most active in combination with ATRi, particularly in the BRCA1/2 mutation subset. Finally, we will use novel protein-based techniques to better understand exactly how the ATR and PARP inhibitors work together, which will permit further improvements of this therapeutic strategy. Our goal is to develop the most effective and well-tolerated treatment of BRCA1/2-mutant ovarian cancers for which standard therapies have faltered.
Children with diffuse midline gliomas continue to have a dismal prognosis and most children die within one year of their diagnosis. Decades of clinical research and hundreds of clinical trials have not been able to change the outcome for these patients. Studies have shown that the majority of these tumors carry a specific mutation referred to as H3.3K27M which is present in almost all tumors cells making this a very attractive target for immunotherapy approaches.
Within this proposal we are aiming to assess the benefit of a specific immunotherapy approach referred to as T cell receptor approach. We have been able to show in the laboratory that this approach is able to kill H3.3K27M tumor cells very effectively. Based on our exciting animal data, we propose to test this new therapy approach in clinic. Subjects whose tumors carry the H3.3K27M will undergo collection of their own T-cells prior to start of radiation therapy, which is considered the standard of care for these tumors. These T cells will subsequently be modified in the laboratory to specifically recognize the specific H3.3K27M mutation. These modified T cells will then be given back to subjects once they completed radiation therapy.
Within this project we will assess if such a therapy approach is feasible and safe. This project has the potential to significantly impact the treatment approach for a disease for which we have not achieved any improvement for the last several decades and is the first of its kind for this devastating disease.
