Q&A with Rhoda Alani, M.D.
By: Diane Bovenkamp
What melanoma research studies are you pursuing at the Kimmel Cancer Center?
My laboratory is studying the molecular signals that initiate and promote the deadly skin cancer, melanoma, which is one of the top ten cancer killers in the United States. My research colleagues and I probe the signals that convert normal skin cells into abnormal melanoma cells and the signals released by tumors to connect to the blood supply to grow larger. We already have identified many cancer-promoting signals present in melanoma cells and are working to create novel drugs to inhibit the progression of melanoma.
Why do you study melanoma? Are there detection methods and cancer treatments already in use?
Scientists at the Johns Hopkins Kimmel Cancer Center are striving to improve the detection, prevention, and treatment of cancer. There are few identified hereditary markers for melanoma, and it occurs at any age – often through "mistakes" in DNA accumulated after years of exposure to sun as well as other environmental and genetic risk factors. While melanoma is one of the fastest growing cancers in the United States, little progress has been made in treating this deadly form of skin cancer. Current traditional radiation and chemotherapy treatments rarely are effective in treating melanomas that have reached later stages, those that have spread to other parts of the body. We, at Johns Hopkins, pledge to improve treatments by understanding the molecular defects that lead to melanoma that will give us the ability to design novel targeted melanoma therapies.
Despite the fact that skin is the most accessible organ and it can be monitored easily, tens of thousands of people die from melanoma each year in the United States. Right now, the best way to find melanoma is to ask a dermatologist to regularly monitor moles and remove those that are irregular or suspicious. Skin cancer is easily curable in early stages, and we are developing clinical tests to detect the first signs of abnormal skin cell behavior that may prevent deadly melanoma from developing or progressing. We also are working to develop several blood tests for the detection of early recurrent disease.
Have you found any proteins that might be useful targets to fight cancer?
One candidate protein family for treatment is called Id. Id proteins are transcription factors, which bind to DNA and turn a gene's expression on or off. Normally, Id1 is a natural control for skin cell growth and renewal. However, a change or mutation in Id1 may cause it to adjust protein expression of the genes it regulates at inappropriate times, promoting abnormal skin cell growth and movement, leading to cancer. My laboratory is performing large-scale studies to confirm our early work that identified Id1 as a good marker for early melanoma in humans. We also are developing a simple rapid diagnostic/prognostic test to be used on patient specimens.
My lab recently completed a gene expression profiling study to compare the molecular signatures of non-invasive and invasive melanomas. We have identified several new candidate genes that may be useful diagnostic/prognostic tumor markers including several proteins that can be detected in the blood of melanoma patients. We also have identified important pathways that lead to melanoma invasion and are working to develop new melanoma treatments based on these discoveries.
Are there other aspects of the Id1 gene pathway that may be good targets for therapy?
My lab found that Id1 regulates expression of a tumor suppressor gene called p16/Ink4a, whose activity is decreased in early stages of melanoma and is mutated in some families with melanoma. We now are evaluating whether targeting Id1 in the skin could increase expression of p16 and possibly prevent progression of melanoma.
Another target of the Id1 gene pathway is thrombospondin-1 (TSP-1), a naturally occurring angiogenesis suppressor. TSP-1 levels are reduced by Id1 during a natural blood vessel-sprouting process called angiogenesis. It is the same process the body uses to repair a cut in a finger, ensuring proper reconnection of vessels essential to healing. When Id1 is expressed, TSP-1 is inactivated and allows for increased growth of blood vessels. Melanoma cells may exploit this natural Id1/TSP-1 signaling to coax blood vessels to sprout toward them, enabling cells to hook up to a nutrient-rich blood supply.
What research is happening now? What are the next steps and plans for the future?
We are studying different stages of melanoma, from benign moles to lethal cancerous growths, to compare the expression of various candidate genes for each stage using DNA and protein microarrays, or “fingerprints”, of the tissues. This should pinpoint the culprit proteins that promote melanoma. Since few diagnostic or prognostic factors exist for this skin cancer, unique tissue protein profiles for each stage of the disease could help suggest the course of treatment – surgery with or without chemotherapy or other treatments.
Once we've found a number of candidate genes, we will work with chemists at Johns Hopkins to design a number of small molecules that will cut off the tumor's signals. These future inhibitors will be tested in animals and then those that are most promising will be translated to clinical trials as quickly as possible.
Cell culture experiments will explore how cancer cells communicate with blood vessels. My laboratory will label blood vessel and tumor cells to monitor how quickly these cells migrate toward each other. The speediest tumor cells, presumably those that are most aggressive, will be evaluated for molecular signatures that enable tumor migration and metastasis. Both RNA and protein “fingerprints” will be used to evaluate these “fast tumor cells.” Cell expression profiles will be determined for tissues collected from all stages of melanoma.
The blood of melanoma patients also will be collected to identify “floating” markers of the cancer. Such a protein, if it promotes early conversion to melanoma, may be a key diagnostic marker, much like prostate-specific antigen (PSA) is used to detect prostate cancer.
Have any of your discoveries had an impact on cancer treatment?
In addition to research, my clinical interests include melanocytic lesions, atypical nevi, and melanoma. I hope to translate my lab discoveries directly into improved treatments for patients. We will do this in collaboration with an expert team at Hopkins, including surgeons, dermatologists, oncologists, radiologists and other researchers. What makes the Johns Hopkins Kimmel Cancer Center unique is its commitment to both laboratory-based and clinical research.
Our research already may be changing the way scientists approach testing cancer drugs in mice. Using two experimental methods widely used by researchers to represent how cancer is formed, we found two different and conflicting results on prior studies of the Id1 gene’s role in angiogenesis. In 2001, we injected cancer cells into mice that lacked Id1 and found that the tumors were dormant (not actively growing). However, in other studies published in 2003, a second mouse model that more accurately represents cancer development revealed that mice lacking Id1 activity actually develop more tumors when exposed to carcinogens over a long period. The two different results suggested that some caution needs to be taken in the choice of cancer models used to test drugs before they are taken to clinical trials. The model of slow carcinogen exposure takes more time in laboratory experiments, but may mimic cancer growth in humans more precisely. My laboratory is continuing studies of the melanoma development and tumor-associated angiogenesis using this improved animal model system.
Visit the Johns Hopkins Melanoma Program web site for more information. | 
