Programs recipients

The Bernice Goldblatt Pediatric Pharmacogentics Program

Principal Investigators: Dr. Ramamoorthy Nagasubramanian, Dr. John Cunningham   ·   University of Chicago

In 2004 the Cancer Research Foundation awarded $500,000 to establish a Pediatric Pharmacogenetics Program at the University of Chicago. The overall goal of this project is to discover molecular determinants that influence anticancer drug response and toxicity in patients with sarcoma.

Total Project Period: July, 2003 through June, 2008

The overall goal of this project is to discover molecular determinants that influence anticancer drug response and toxicity in patients with sarcoma. The dramatically different clinical courses of sarcoma patients treated with the comparable, intensive, multi-agent chemotherapy regimens likely represents a molecular heterogeneity that has not been appreciated in studies using conventional methods of characterizing tumor biology. We will identify genetically inherited traits and molecular determinants that influence drug response and outcome in sarcoma patients with the ultimate goal of identifying subsets of patients that are at high risk of treatment related toxicity or failure. The identification of heritable factors influencing susceptibility to drug toxicity will ultimately lead to the development of safer drug regimens in children and adults and offer the potential for new agent development. A clinical by-product will be the treatment of children and adults with sarcoma according to risk-adapted therapy that involves tailoring the intensity of multi-agent chemotherapy protocols to each patient's risk of relapse and toxicity. Support from the Cancer Research Foundation to establish The Bernice Goldblatt Pediatrics Pharmacogenetic Program will enable us to implement a novel strategy for the classification and treatment of sarcoma patients at the University of Chicago.

Sarcomas comprise a wide range of tumors including bone sarcomas (osteosarcoma), soft tissue sarcomas, rhabdomyosarcoma and Ewing's sarcoma. As a pilot, we will test the above hypothesis in pediatric/adolescent osteosarcoma and extend the model to study other childhood and adult sarcomas.

Osteosarcoma is the most frequent primary malignant bone tumor, with most tumors diagnosed in the second decade of life. About 15-20% of patients with osteosarcoma present with detectable metastatic disease at diagnosis. Only 60-65% of newly diagnosed patients with non-metastatic osteosarcoma are cured by surgery and multi agent chemotherapy. Survival in patients with metastatic disease at presentation remains discouragingly low at 25% and is even lower in patients who relapse after initial therapy. Current standard therapy for osteosarcoma involves preoperative multi-agent chemotherapy, definitive surgery and post-operative chemotherapy based on tumor response noted at surgery. Patients with good response to therapy, defined as those with >90-98% tumor necrosis at definitive surgery, have a >80% disease free survival (DFS) while poor responders continue to have a 40-60% DFS. The majority of patients are poor responders. More intensive therapy and therapy with new agents is the new approach for the poor responder patients but these will lead to a heightened risk of toxicity.

The inability to differentiate the good from the poor responders at diagnosis remains a major limitation in the treatment of patients with ostesarcoma. Using gene expression profiling experiments at diagnosis, we will identify the subset of patients that would be at high risk of treatment failure, and design protocols tailoring the intensity of pre-operative chemotherapy to risk and thereby improve response rates and survival. This strategy will also identify good risk patients that could receive non-intensive chemotherapy and be spared from additional toxicities like cardiotoxicity and ototoxicity. Results from our pharmacodynamic polymorphism discovery experiments in combination with tumor gene expression array analysis will help us develop more efficient and safer treatment protocols for children and adults with osteosarcoma leading to improved overall survival.

The aim of this proposal is to discover the heritable traits and molecular determinants influencing responses to anticancer agents used in the treatment of sarcomas. We initially plan to study osteosarcoma and apply the model to other sarcomas of children and adults. The long-term goal is to enhance the efficacy and safety of the currently used multi-agent chemotherapy regimens to improve the outcome and survival of children and adults with cancer. This research has three specific aims:

  • Specific aim 1 To enhance risk assessment at diagnosis by developing prognostic indicators predictive of response and outcome, using tumor gene expression profiling, at diagnosis, in children and adolescents with osteosarcoma
  • Specific aim 2 To discover pharmacodynamic polymorphisms and molecular determinants influencing responses to anticancer agents used in the treatment of osteosarcoma
  • Specific aim 3 To develop a risk adapted, tailored clinical protocol for the treatment of children and adolescents with osteosarcoma