Oncology Program

Vitamin D has compelling potential for use in treating cancer. Epidemiological studies provide strong evidence that calcitriol, the active form of vitamin D, reduces the incidence of common human cancers, including carcinomas of prostate, breast, colon and lung. The potential role of vitamin D in the treatment of cancer is also supported by a large number of in vitro and in vivo studies characterizing its ability to control processes involved in tumorigenicity, such as proliferation, differentiation, apoptosis, angiogenesis and metastasis.

Despite potential benefits of vitamin D in chemoprevention and therapy, clinical use of calcitriol is potentially problematic due to dose-limiting side-effects such as hypercalcemia and hypercalciuria. Because of these side-effects, vitamin D therapies are customarily administered at low dosages, which at times are ineffective. Starting dosage is increased cautiously, if at all, to minimize the occurrence of these toxic side effects, rather than to optimize therapeutic response. Alternatively, high-dose calcitriol treatment can be used but only intermittently in order to allow normalization of serum calcium levels.

An additional complication in vitamin D therapy is the rapid metabolism of vitamin D by the CYP24 enzyme. CYP24 is one of the best known examples of a calcitriol-inducible gene and is directly responsible for calcitriol metabolism intracellularly. It is well documented that calcitriol, acting via its receptor, transcriptionally up-regulates the expression of the CYP24 gene and thus promotes its own metabolism which can compromise the clinical effectiveness of calcitriol leading to gradual development of treatment resistance. CYP24 is also considered as a candidate oncogene.

These observations suggest that 1) certain tumors may be resistant to calcitriol prior to treatment and 2) CYP24 inhibition will be beneficial in vitamin D-based cancer prevention and therapies.

Perceiving the limitations of current vitamin D-based therapies, Cytochroma, in collaboration with Prof. Gary H. Posner at The Johns Hopkins University, has developed a family of novel vitamin D analogs that combine potent agonist activity with the ability to strongly and selectively inhibit CYP24 enzyme. These are efficacious and safe compounds exhibiting lower calcemic potential than clinically-used vitamin D compounds. Several compounds, all potent agonists and efficient inhibitors of the CYP24 enzyme, have demonstrated tumor growth inhibition in vitro and in vivo.

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