Supportive Care in Cancer Treatment

The side effects that accompany cancer treatments involving ionizing radiation or chemotherapy present significant health issues and limit the dose (and therefore effectiveness) of the treatment. These side effects are largely determined by stress-induced apoptotic death of normal cells in sensitive tissues. CBLI’s Protectan compounds specifically inhibit this process, while not affecting therapy-induced killing of tumor cells. Thus, these compounds have strong potential to play a major role in medical applications as an adjuvant to cancer therapy.
Given the prevalence of cancer (approximately 1.4 million new cases each year in the U.S. alone) and the fact that more than 70% of patients are impacted by treatment side effects, there is a significant global market for drugs that limit side effects and, therefore, allow more intense and effective treatment regimens. Cancer treatment side effects largely result from stress-induced apoptosis of normal cells in sensitive tissues. This includes intestinal cells (leading to nausea), hair follicles (leading to hair loss), spermatocytes (leading to male infertility) and hematopoietic (HP) cells (leading to immunosuppression).

The factor that typically determines the dose limits for radiation therapy is the onset of gastrointestinal (GI) syndrome (abdominal pain, nausea, diarrhea, vomiting accompanied by systemic effects such as malabsorption, dehydration, bowel obstruction, anemia, bleeding, sepsis, etc.) due to loss of the epithelial cells lining the GI tract. Pharmacological protection of these cells would allow for increased radiation doses to more effectively eliminate tumor cells. This, of course, requires that the drug does not also act as a radioprotectant in tumor cells.

CLBI’s Protectans technology presents an ideal strategy for counteracting cancer treatment side effects. While normal “bystander” tissues are damaged by cancer treatments through apoptotic cell loss, most tumors have defects in their apoptotic machinery and are killed through non-apoptotic mechanisms. Thus, Protectans that are designed to imitate survival mechanisms developed by tumor cells – suppression of apoptosis via inhibition of p53 and/or activation of NF-kappaB – would be expected to protect normal, but not tumor, cells.
Indeed, CBLI has shown both in vitro and in vivo that its lead Protectan, CBLB502, protects normal cells of both the GI and HP systems from radiation-induced cell death, yet has no effect on the radiosensitivity of a diverse set of tumor cell types. For example, in mouse models, tumors can be eliminated by radiation treatment; however, this “therapeutic effect” is accompanied by death due to radiation toxicity. Treatment with CBLB502 together with radiation allows the mice to survive while tumor cells are eliminated. CBLB502 is an optimized derivative of bacterial flagellin that signals through the TLR5 cell surface receptor to activate the anti-apoptotic NF-kappaB pathway.

Radioprotective doses of CBLB502 are non-toxic and non-carcinogenic. The compound provides long-term radioprotection with no development of delayed-onset radiation-induced sickness. Moreover, CBLI has demonstrated that the drug is effective against multiple fractionated doses of radiation mimicking typical cancer therapy regimens and that repeated administration of CBLB502 does not diminish its activity.
CBLI has also shown that CBLB502 ameliorates radiation-induced neutropenia, which is also a significant adverse side effect of chemotherapy. Thus, CBLB502 may be useful as an adjuvant to chemotherapy in addition to radiation therapy.

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