Modulation of Therapeutic Response

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In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. We have recently shown that loratadine, halofuginone, and guggulsterone enhance tumor cell radiation response in vitro. These agents enhance radiosensitivity by different mechanisms including cell cycle redistribution, inhibition of radiation-induced repair, and inhibition of TGF-beta signaling. A molecularly targeted Chk-1 inhibitor has demonstrated significant radiosensitive in p53 mutated human tumor cell lines. Normal human fibroblasts (p53 wild type) are not radiosensitized by this agent suggesting differential tumor sensitization. This agent also provides considerable radiation enhancement in vivo with very little to no normal tissue toxicity. While this agent abrogates the normal radiation-induced delay in G2 of the cell cycle, inhibition of repair of radiation damage appears to be the major mechanism of radiosensitization. In collaboration with the Radiation Oncology Branch a clinical trial is being submitted to evaluate this agent in colorectal cancer. We are also evaluating a CK2 inhibitor and preliminary data show this agent to be an effective in vitro radiation sensitizer of human tumor cell lines. Preliminary studies are underway evaluating an IGF-1R antibody, an anti-angiogenesis agent, and an epilone analogue as radiation modifiers. With respect to normal tissue response to radiation, it is widely known that the TGF-beta signaling pathway is a major player in radiation-induced late effects (fibrosis). Our previous studies have shown that mice deficient in TGF-beta signaling (Smad3 knock-out mice-downstream signaling intermediate in the TGF-beta pathway) are resistant to fibrosis when treated with high dose radiation. Recent mouse normal tissue studies using a TGF-beta type 1 receptor kinase inhibitor have shown marked reduction in radiation-induced soft tissue fibrosis. This agent blocks the TGF-beta signaling pathway. Lastly we have preliminary pre-clinical data suggesting that the nitroxide, Tempol (both systemic and topically applied) protects against radiation-induced oral mucositis. Oral mucositis is a common toxicity associated with the radiation treatment of head and neck cancers. We have also shown in preliminary studies that Tempol does not alter chemoradiation with respect to tumor regrowth delay, providing more data to introduce these experimental agents into human radiation oncology clinical trials.