This page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
Conclusions
After researching malignant melanoma, I found the prognosis statistics to be very interesting and quite frightening. Only 14% of people who develop metastatic melanoma will survive five years. Given this fact, I decided to focus on treating and curing melanoma using a genetic approach for my project.
Using STRING 9.0, I found that CDK4 is in CDKN2A's interaction network in both humans and mice. CDKN2A binds to CDK4 and inhibits it in order to regulate the cell cycle. When a mutation in CDKN2A leads to the loss of its function, CDK4 cannot be inhibited by this specific interaction. This is the mechanism in which many patients with familial melanoma develop cancer. When we studied chemical genetics in this course, I was intrigued by the possibility of developing a drug to inhibit CDK4 in patients with high risk of melanoma due to a mutation in the CDKN2A gene. I found a compound that is known to inhibit CDK4 in PubChem called CDK4 Inhibitor III. I designed my experiment around this discovery.
I hypothesized that CDK4 Inhibitor III could be used as the active ingredient in a drug to treat melanoma in patients with loss of function of CDKN2A. To test this hypothesis, I designed an experiment using conditional knock out nude mice that have CDKN2A knocked out in their skin. After grafting a melanoma tumor onto the mice, I would administer the drug and observe metastasis as well as gene expression of CDKN2A and CDK4 using micro array technology. I would expect that the mice that received the drug would have less melanoma metastasis than the mice that did not received the drug. I chose mice as a model system because their skin and vascular system provides a great model to study skin cancer and metastasis. Also, as previously mentioned, the interaction between CDKN2A and CDK4 is conserved in mice, which is necessary for my idea of drug development.
Please see a copy of my final presentation below.
Using STRING 9.0, I found that CDK4 is in CDKN2A's interaction network in both humans and mice. CDKN2A binds to CDK4 and inhibits it in order to regulate the cell cycle. When a mutation in CDKN2A leads to the loss of its function, CDK4 cannot be inhibited by this specific interaction. This is the mechanism in which many patients with familial melanoma develop cancer. When we studied chemical genetics in this course, I was intrigued by the possibility of developing a drug to inhibit CDK4 in patients with high risk of melanoma due to a mutation in the CDKN2A gene. I found a compound that is known to inhibit CDK4 in PubChem called CDK4 Inhibitor III. I designed my experiment around this discovery.
I hypothesized that CDK4 Inhibitor III could be used as the active ingredient in a drug to treat melanoma in patients with loss of function of CDKN2A. To test this hypothesis, I designed an experiment using conditional knock out nude mice that have CDKN2A knocked out in their skin. After grafting a melanoma tumor onto the mice, I would administer the drug and observe metastasis as well as gene expression of CDKN2A and CDK4 using micro array technology. I would expect that the mice that received the drug would have less melanoma metastasis than the mice that did not received the drug. I chose mice as a model system because their skin and vascular system provides a great model to study skin cancer and metastasis. Also, as previously mentioned, the interaction between CDKN2A and CDK4 is conserved in mice, which is necessary for my idea of drug development.
Please see a copy of my final presentation below.
melanomapresentation.pptx | |
File Size: | 1994 kb |
File Type: | pptx |
Future Directions
There are a number of things that I would like to continue to research regarding melanoma and CDKN2A. First of all, I would like to study different modes of drug administration such as an intravenous solution versus a topical cream as well as different dosage regimens. Also, I would like to study other proteins that interact with CDKN2A and CDK4. There is a large network with a lot of conservation between humans and mice so it would be interesting to understand the function of other proteins in the network. I think it would be particularly interesting to study other potential tumor suppressors in the network. As many people know, exposure to UV light is highly associated with the development of melanoma. It would be very interesting to study the effects of UV exposure in people with a CDKN2A mutation, as well as UV protective agents such as sunscreen products.
References
Cabanillas, Rubén et al. (2011). Novel germline CDKN2A mutation associated with head and neck squamous cell carcinomas and melanomas. Head and Neck. doi: 10.1002/hed.21911
Lesueur, F et al. (2008). The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma. British Journal of Cancer. 99(2), 364-70. doi: 10.1038/sj.bjc.6604470
Miller, A et al. (2006). Melanoma. The New England Journal of Medicine. 355(1), 51-65. PMID:16822996
Reginster, M et al. (2011). Molecular Dermapathology in Malignant Melanoma. Dermatology Research and Practice. 2012(684032). doi:10.1155/2012/684032
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001853/
http://www.aad.org/skin-conditions/dermatology-a-to-z/melanoma/signs-symptoms/melanoma-signs-and-symptoms
http://www.cancer.gov/cancertopics/pdq/genetics/skin/HealthProfessional/page4#Section_165
Cabanillas, Rubén et al. (2011). Novel germline CDKN2A mutation associated with head and neck squamous cell carcinomas and melanomas. Head and Neck. doi: 10.1002/hed.21911
Lesueur, F et al. (2008). The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma. British Journal of Cancer. 99(2), 364-70. doi: 10.1038/sj.bjc.6604470
Miller, A et al. (2006). Melanoma. The New England Journal of Medicine. 355(1), 51-65. PMID:16822996
Reginster, M et al. (2011). Molecular Dermapathology in Malignant Melanoma. Dermatology Research and Practice. 2012(684032). doi:10.1155/2012/684032
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001853/
http://www.aad.org/skin-conditions/dermatology-a-to-z/melanoma/signs-symptoms/melanoma-signs-and-symptoms
http://www.cancer.gov/cancertopics/pdq/genetics/skin/HealthProfessional/page4#Section_165