Project Funding Details

Background: In 2009, CancerFree Kids Foundation funded our pilot study to generate preclinical data to support the development of a phase I study of the telomerase inhibitor, Imetelstat. Our data strongly suggest that the inhibition of telomerase, a cancer-associated enzyme, with Imetelstat combined with ionizing radiation is an effective way to increase the efficacy of radiotherapy (RT) by lowering radiation doses and therefore minimizing the devastating side effects of RT. Telomerase inhibition has never been used to treat pediatric cancers. We seek funding to conduct the proposed correlative studies of Imetelstat in the first national Phase I study conducted in childhood cancers through the Children’s Oncology Group (COG, ADVL1112). This study has been approved by Cancer Therapy Evaluation Program (CTEP) and will be open nationally to patient enrollment in mid-2011. The COG and CTEP will pay for the conduct of the clinical trial but not for the associated correlative studies which my laboratory will be conducting in tumors and blood samples of consenting patients. Rationale: Telomerase is an enzyme that maintains telomere length in the vast majority of cancer cells. Telomeres are specialized structures found at the end of chromosomes that are involved in the replication and stability of the chromosomes. Since telomerase is undetectable in most normal human tissues, whereas it is specifically activated in more than 90 % of cancer-derived cell lines and malignant tumors, this enzyme is a rational target for the treatment of cancers. Inhibition of telomerase activity in cancer cells results in cessation of their ability to maintain telomere length and eventually stop dividing and die. Multiple studies with tumors growing in mice in a wide variety of cancer models have demonstrated that Imetelstat inhibits tumor growth, and prevents metastases. Additionally, studies with cancer cells growing in the dish as well as with tumors growing in mice have shown that Imetelstat is an effective inhibitor of multiple cancer stem cell types. Purpose: The primary objectives of the Phase I study are to estimate the maximum tolerated dose and recommend a Phase II dose of Imtelstat in children with recurrent or refractory solid tumors. The purpose of this application is to measure telomerase inhibition by Imetelstat in participating patient’s tumor and blood samples. Experimental Design: Using various molecular biology techniques and enzymatic assays, telomerase activity, telomere length and expression of components of telomerase enzyme will be assessed in tumor tissues and in blood samples prior to and following therapy with Imetelstat. Imetelstat will be administered on days 1 and 8 every 21 days. Significance and Future Plans: Once we determine the optimal dose of Imetelstat in children with recurrent cancer in the proposed study, we will be able to conduct studies of imetelstat in combination with RT in virtually all pediatric solid tumors where telomerase is activated. Our primary goal, however, is to use Imetelstat combined with RT in children with poor-prognosis brain tumors to lower radiation doses, diminish RT’s side effects, and ultimately to improve outcome as well as quality of life in these vulnerable children. The data from this proposal will be used to garner extramural grant support for a Phase II clinical trial which could ultimately lead to FDA approval of Imetelstat for the treatment of certain cancers.