Targeting of DNA has been one of the most successful approaches in the systemic treatment of cancer. However, this approach entails significant toxicities as these agents do not distinguish between the DNA of normal cells and cancer cells. Consequently, normal tissues will frequently be damaged (e.g. alkylating agents, antitumor antibiotics etc). The telomere, a DNA structure, and proteins binding to the telomere (e.g. telomerase) are attractive targets for drug development as they contain features that appear unique to the cancer cell and accessible to pharmacologic agents. The majority of cancers (>85%) overexpress telomerase which is essential to maintain telomere length and allow for indefinite cell proliferation. Most normal cells lack telomerase activity. Abnormal expression has been clearly documented in lung cancer, the most lethal malignancy in the United States. Additionally, recent data indicates that expression of telomere-associated proteins is prognostic for non-small cell lung cancer. We and others have demonstrated that arsenicals and cisplatin can directly bind to telomeres and inhibit telomerase, leading to telomere shortening and cell death. Susceptibility to this effect is related to initial telomere length. Furthermore, we have demonstrated that the combination of cisplatin and sodium metaarsenite (KML001), an orally available agent, is synergistic. Based upon our preclinical data we hypothesize that KML001 will affect telomeres and telomerase in cancer cells, that the combination of KML001 and cisplatin will be advantageous and that we will be able to identify a population of patients who will be susceptible to this treatment. To test these hypotheses, we propose to evaluate the clinical and biological activity of the telomere targeting agent KML001 in non-small cell lung cancer. An initial trial in advanced cancer will determine the tolerability of this agent in combination with cisplatin as well as provide information regarding factors predictive of clinical benefit from this combination. We will first perform a phase I trial combining KML-001 and cisplatin to determine the maximum tolerated doses of this combination and perform pharmacokinetic and preliminary pharmacodynamic studies. We will then perform a limited trial of KML001 in combination with cisplatin as preoperative therapy in early stage lung cancer. Our goal is to demonstrate that this approach may improve outcome in lung cancer, the most common cause of cancer death in the United States.
Targeting of DNA has been one of the most successful approaches in the systemic treatment of cancer. However, this approach entails significant toxicities as these agents do not distinguish between the DNA of normal cells and cancer cells. Consequently, normal tissues will frequently be damaged. The telomere, a DNA structure, and proteins binding to the telomere (e.g. telomerase) are attractive targets for drug development as they contain features that appear unique to the cancer cell and accessible to pharmacologic modulation. The majority of cancers (>85%) overexpress telomerase, an enzyme, that is essential for maintaining telomere length and for indefinite cell proliferation. Most normal cells lack telomerase activity. Abnormal expression of telomerase has been clearly documented in lung cancer, the most lethal malignancy in the United States. This study will explore the use of a telomere targeted agent, KML-001 in combination with cisplatin in lung cancer.
| Kim, Grace J; Koshy, Matthew; Hanlon, Alexandra L et al. (2016) The Benefit of Chemotherapy in Esophageal Cancer Patients With Residual Disease After Trimodality Therapy. Am J Clin Oncol 39:136-41 |
| Wakelee, Heather; Kelly, Karen; Edelman, Martin J (2014) 50 Years of progress in the systemic therapy of non-small cell lung cancer. Am Soc Clin Oncol Educ Book :177-89 |
