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.
We have recently discovered that tumors cells with integrin αvβ3 on their surface are particularly difficult to treat because αvβ3 triggers reprogramming events that make tumors immune to certain anti-cancer therapies. Because we identified the pathways by which integrin αvβ3 drives these changes, we were able to reverse this behavior in preclinical research models by re-purposing FDA-approved drugs developed for other indications. Now, funding from the V Foundation will allow us to test whether this strategy can be translated to improve the response to therapy for patients with non-small cell lung cancer.
To do this, we will first look for the presence of integrin αvβ3 on circulating tumors cells that may be present in blood samples from patients who have become resistant to a targeted form of cancer therapy called Erlotinib. Once optimized, this assay could be used as a non-invasive blood test to identify the earliest emergence of drug resistance in lung cancer patients. Next, we will conduct a Phase II clinical trial to test if patients who have developed resistance to Erlotinib can be “re-sensitized” to the drug by adding a second drug, an inhibitor of the NFκB pathway known as VELCADE. According to our preclinical animal studies, we expect the addition of this FDA-approved drug will allow patients to respond to Erlotinib therapy for a much longer time.
Since there is no clearly defined standard of care therapy for Erlotinib-resistant lung cancer, our project will address this unmet need and, if successful, would change the way lung cancer patients are diagnosed and treated.
We are proposing in this V Foundation Translational Grant application to continue to transition C188-9, a small-molecule inhibitor of the cancer-causing protein, Stat3, into an oral drug for use in treating patients with breast cancer and cancer cachexia. The target cancer is a subtype of breast cancer for which there currently are no available targeted therapies in the clinic i.e. breast cancers that do not express the estrogen receptor (ER-), the progesterone receptor (PR-) or the human epidermal growth factor receptor (HER) 2 receptor (HER2-). This subtype of breast cancer, often referred to as triple-negative breast cancer (TNBC), accounts for 20% of breast cancer, is characterized by an aggressive phenotype, is preferentially found in younger women and in African-American women, and has been associated with poor prognosis. Recent studies by us and others has demonstrated that Stat3 is activated in 70% of TNBC tested and that Stat3 activity makes a critical contribution to the growth of these tumors. Thus, Stat3 may be a key target in this subtype of breast cancer. We have developed the capability of testing C188-9 for its ability to inhibit the growth in mice of TNBC tumors that have been transplanted directly from patients. This capability allows us to determine accurately whether or not a patient with TNBC will respond to C188-9. Thus far, we have tested C188-9 in two TNBC patient-derived xenograft (TN-PDX) models in which activation of Stat3 was demonstrated. One TN-PDX model was resistant to standard chemotherapy (docetaxel), while the second TN-PDX model was sensitive to docetaxel. We observed a striking benefit in both models when C188-9 treatment was added to docetaxel. The docetaxel-resistant TN-PDX was converted to docetaxelsensitive by the addition of C188-9, while the docetaxel responsive TN-PDX demonstrated an improved tumor response by shrinking 4-fold further with the addition of C188-9. We have determined that C188-9 given by mouth at high doses is quite safe in mice, rats and dogs. C188-9 also reached high levels in the bloodstream and tumors borne by these animals with 2-fold higher levels being achieved in the tumors than in the bloodstream. As outlined in this proposal (Aim 1), we plan to perform an animal clinical trial using 23 TN-PDX models, and thereby learn the breadth of responses to C188-9 we can expect in patients with TNBC. This information will be very useful for designing clinical trials to test the effect of C188-9 in combination with docetaxel in TNBC patients. The animal clinical trial will also allow us to determine if reduction in the level of activated Stat3 in blood cells and in tumors can serve as a marker that we can follow in patients as evidence of successful targeting of Stat3 by C188-9.
Cachexia is the second clinical application for C188-9 that we are exploring in this proposal. Cachexia is the muscle wasting process causing progressive muscle weakness in nearly all patients with cancer. Cancer cachexia is a major cause of morbidity and reduced quality of life in patients with cancer, including breast cancer, and it directly causes up to 25% of all cancer deaths. We recently demonstrated that cachexia in cancer involves a signaling pathway within skeletal muscles that links Stat3 activation with upregulation of myostatin, a hormone that serves as the major negative regulator of muscle mass. Targeting myostatin in mouse models of cancer cachexia not only reversed cachexia but also improved survival despite continued growth of tumor. However, patients with cachexia who have been treated with direct myostatin inhibitors developed unexplained bleeding, which has halted further testing of this approach. We demonstrated that C188-9 treatment of mice with tumors that cause cachexia prevents activation of Stat3 within their skeletal muscles. Consequently, levels of myostatin were not increased and muscle wasting was prevented. Importantly, treatment with C188-9 did not cause any ill effects in mice. In fact, tumor-bearing mice treated with C188-9 gained weight and maintained muscle strength. One of the goals of the clinical trials outlined in Aim 2 of this proposal is to begin to determine if C188-9 treatment of patients with TNBC prevents them from developing muscle loss, weakness, and/or fatigue.
The successful completion of the studies outlined in this proposal will provide additional strong support for the overarching concept that C188-9 can be used safely and effectively as an oral agent to treat patients with breast cancer, particularly TNBC, in combination with standard chemotherapy to improve therapeutic responses, as well as to prevent cancer cachexia.
In the era of Precision Medicine, the treatment of Acute Myeloid Leukemia (AML) remains a significant challenge with fewer than 50% of patients having long term disease-free survival. Yet, the explosion of genomic information has allowed us to refine our knowledge of the genetic changes that result in the development of the many subsets of AML and has provided us insights into new and potentially groundbreaking clinical advances. One of the most common subsets of AML that affects both children and adults is characterized by mutations in a gene important for normal blood cell growth and development known as FLT3. The FLT3 gene is mutated or abnormally expressed in up to 25% of cases of AML and this abnormal expression results in an aberrantly active FLT3 kinase that results in a rapidly proliferating AML with a poor treatment outcome in all patient age groups. Therefore, specific therapies for FLT3 mutant leukemias are needed urgently. Attempts to target the mutant FLT3 with targeted FLT3 kinase inhibitors is an area of active research but a major breakthrough has not yet been made; in part, this is due to the rapid emergence of resistance to the targeted FLT3 kinase inhibitors that have thus far been tested. In this application, we propose the development of a new agent to treat leukemias with mutation or over-expression of FLT3. Recently, our group identified that a protein kinase, known as TOPK, which is abnormally expressed in many cancers (but not in normal tissues) is also expressed in high levels in AML, particularly in AML cells with mutations of FLT3. The laboratory of Dr. Yusuke Nakamura, one of the principal investigators of this grant identified a specific inhibitor of TOPK which is now being developed in partnership with a Japanese company, OncoTherapy Science. They are now completing toxicity and large animal model feasibility testing. Importantly, Dr. Nakamura’s laboratory has developed other successful new protein kinase inhibitors in collaboration with OncoTherapy Science, including a MELK protein kinase inhibitor that is currently being tested for the first time in patients with a variety of solid tumor malignancies here at the University of Chicago. We have tested the TOPK inhibitor OTS514 in many AML cell lines and in cells from patients with AML. Interestingly, this TOPK inhibitor has tremendous activity against AML cells, particularly in those with FLT3 mutations, resulting in their cell death using clinically achievable concentrations of the drug. Importantly, the TOPK inhibitor, OTS514, does not impair the survival of normal early blood cells. The goal of our grant is to understand how it is that the TOPK inhibitor kills FLT3 driven leukemias, to perform pre-clinical testing of OTS514 in mouse models of FLT3 leukemias and, using these insights, to design and perform a first in human trial of this TOPK inhibitor in patients with AML, focusing on those with mutations in FLT3. Our proposal is a comprehensive bench to bedside approach! The ability to shut down FLT3 expression with TOPK inhibition also provides the potential for circumventing the resistance that occurs with targeted FLT3 kinase inhibitors. Thus, we are optimistic that understanding of the mechanism by which TOPK impairs FLT3 driven leukemia cell growth and survival and the performance of a phase I “first in human” trial will provide us with the insights needed for future successful development of this TOPK inhibitor, with the ultimate goal of using a Precision Medicine approach to improving the survival of patients with FLT3 mutated AML.
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