Children with diffuse intrinsic pontine glioma– a specific brain tumor type- continue to have a dismal prognosis and most children die from this disease within months from diagnosis. Despite multiple national clinical trials, no change in outcome has been achieved over the last several decades. Two potential reasons why we have not made any progress in this disease are a) treatment is not matched to each child’s individual tumor characteristics and b) due to the presence of a tight blood-brain barrier medications given either by mouth or vein are not getting in sufficient enough concentrations to the tumor. To address these issues we are currently conducting a clinical trial through the Pacific Neuro-Oncology Consortium (www.pnoc.us, PNOC003). In this trial we will profile each child’s tumor with state of the art next generation sequencing and determine a treatment plan based on the specific characteristics of the tumor. A specialized tumor board that consists of several neuro-oncologist, pharmacologists and researches with an expertise in next generation sequencing meet and discuss the results and determine a specialized treatment plan, which consists of up to four FDA approved drugs. Specific attention is being paid to the drug brain penetration of recommended drugs. Correlative aims of this feasibility study is to develop patient derived mouse models as well as to test if tumor specific DNA can be detected in blood and be used as a marker for clinical response.
Almost all cells of an individual share the same genetic information. Yet each individual has many different cell types with distinct characteristics and functions (e.g. skin cells and brain cells of the same individual are indistinguishable genetically). One the most vexing questions in biology is: how is this dizzying array of cell types made within an individual, all of which come from the same blueprint of genetic information? We now know what differs among the different cell types of an individual is not the genetic information; instead, it is the ‘on’ and ‘off’ state of genes in that cell type. In other words, a cell’s unique gene expression signature determines its characteristics. A molecular memory system, called epigenetics, establishes and remembers the cell type’s unique gene expression pattern during development. One way by which cells become cancerous is by losing their ability to remember who they are. This also impairs their ability to protect their DNA against damage and instability. Recent work has revealed the identity of some proteins whose job is to regulate these important processes. We have found that two of these proteins work together to create a special DNA structure, which protects our DNA against instability and remembers if a gene is ‘on’ or ‘off’. We plan to understand the mechanism by which these and other proteins regulate gene expression and genome stability. This work impacts our basic understanding of many different cancers, and will likely allow the development of new drugs and new strategies for killing or reprogramming cancer cells.
Bladder cancer patients experience widely variable clinical outcomes. Some are cured of their disease with surgery alone, whereas others require chemotherapy, and only about half of individuals who receive chemotherapy benefit from it. These differences in clinical behavior are almost certainly based in differences in cancer biology, and the overall goal of our bladder cancer research program is to deeply define them so that optimal therapeutic approaches can be offered to each patient. We recently discovered that bladder cancers can be grouped into “intrinsic subtypes” that are remarkably similar to the ones that exist in breast cancers. One of the bladder cancer subtypes (“p53-like”) is similar to “luminal A” breast cancers, and like them, tend to be resistant to chemotherapy and metastasize to the bone. Their most distinguishing feature is that they contain large numbers of normal cells (termed “fibroblasts”) that are being implicated in drug resistance and bone metastasis in laboratory models of other types of cancer (including breast cancer). In this project we will examine further whether the p53-like tumors are chemo-resistant and metastatic to bone by analyzing several additional cohorts of patients treated with chemotherapy in clinical trials. Then we will directly examine the contributions of the fibroblasts to chemoresistance and bone metastasis in laboratory models. Our goal is to use the information to distinguish patients who will benefit from chemotherapy from those who will not. And by studying the biological mechanisms influenced by the fibroblasts, we should be able to identify new, more effective therapies for patients with chemoresistant bladder cancers.
Leukemia stem cells (LSCs) are able to regenerate leukemia after chemotherapy and cause leukemia relapses. LSCs are transformed from the normal blood stem cells by mutations. We found that one of the commonly found mutations NRAS is able to re-program the signaling pathways in normal blood stem cells and chamge them into LSCs. Our studies showed that Nras does this through an unexpected pathway and targeting this pathway may lead to elimination of LSCs to potentially cure leukemia.
Alveolar rhabdomyosarcoma is one of the most common children tumors. No effective therapy is available for advanced disease. Poor understanding of the etiology of the tumor is partly responsible for the lack of advancement in treatment. We are using tumor-signature events to study the cell of origin for the disease. Our results may shed light on the development of the tumor, and potentially lead to better diagnostic and therapeutic tools.
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.
