Non-melanoma skin cancers (NMSCs), which include both basal cell (BCCs) and squamous cell carcinomas (SCCs), are the most common skin neoplasm. Environmental ultraviolet B (UVB) exposure is the main etiologic factor for these skin cancers. However, other environmental and genetic factors also affect their susceptibility. In organ transplant recipients (OTRs) the incidence of these cancers increases by 10 to 250 fold. In addition, these tumors become more aggressive/invasive and metastatic ultimately contributing to augmented morbidity and mortality in this already morbid population. These cancers in OTRs are not only originated from the carcinogenic exposure of the transplant recipient but may also be contributed by the donor organ. Circulating tumor cells have also been found in these patients. At present at least 500,000 OTRs are living in the USA and their number is growing every year. Skin cancer is the most frequently occurring neoplasm in this population. Therefore, prevention of skin cancer is desperately required in this population. Oral retinoid showed some success in this regard however, their administration cause severe toxicity particularly hyperlipidemia. Here at the University of Alabama at Birmingham, we have developed a relatively non-toxic retinoid without compromising its efficacy. UAB30, a 9-cis retinoic acid was found to be well-tolerated in humans and in experimental animals and showed no significant toxicity as compared to placebo group. We, therefore propose here to test the hypothesis that UAB30 may be highly effective in preventing BCCs and SCCs in chronically immuno-suppressed mice and acts by inducing DNA damage response (DDR) signaling besides activating RAR/RXR pathway. For this, we have developed novel genetically engineered Ptch1+/-/SKH-1 mice, which following chronic UVB irradiation, develop both BCCs and SCCs. We also have compelling preliminary data to support our hypothesis.
Three specific aims are proposed.
Specific Aim 1 will investigate the effects of UAB30 on development of BCCs/SCCs in chronically immuno-suppressed UVB-irradiated Ptch1+/-/SKH-1 mice.
Specific Aim 2 will investigate the molecular mechanisms by which UAB30 mediates skin cancer prevention. In preliminary studies, we found that UAB30 induces DDR signaling. We will therefore assess whether these responses are identical in immuno-competent and immuno-suppressed animals.
Specific Aim 3 will unravel the molecular basis for the pharmacological action of UAB30 in the experiment settings of normal and immuno- suppression using in vitro/in vivo approaches. We will study whether alterations fanconi anemia DNA damage repair pathway are important mechanistic component underlying efficacy of UAB30. In summary, studies proposed here will not only demonstrate the preclinical efficacy of UAB30 in chronically immuno-suppressed mice but will also address its molecular mechanism dependent/independent of RAR/RXR.
Non-melanoma skin cancers (NMSCs) including both basal cell (BCCs) and squamous cell carcinomas (SCCs), are the most common skin neoplasm, the incidence of which increases in organ transplant recipients (OTRs) by 10 to 250 fold, and these tumors become more aggressive/invasive and metastatic contributing to augmented morbidity and mortality in this already morbid population. Prevention of skin cancer in this population is desperately required. UAB30, a well-tolerated 9-cis retinoic acid which we found to act via a novel mechanism may be a potential candidate for blocking skin cancer progression in chronically immuno- suppressed mice and perhaps in OTRs.
