Medical Minute 6-27: Treating Melanoma With DNA

By: Vanessa Welch Email
By: Vanessa Welch Email

63-year-old Michael Sosnowicz never imagined that something he did when he was his children's age could kill him decades later. Sosnowicz spent years in the sun at his family's marina.

"The way I looked at things, you can't hurt Superman," said Michael Sosnowicz.

Thirty years ago, doctors removed a cancerous tumor from Sosnowicz's leg and told him he was cured.

"Last April or May, I was driving home, and I put my hand on my thigh. Right here, next to the excision spot, I felt what I thought was a lipoma -- a fatty tumor."

Doctor Lynn Schuchter is a melanoma expert at the University of Pennsylvania. She says the biggest breakthrough in decades may lie within a patient's DNA. Forty percent of the patients with melanoma have a broken gene-called the B-RAF gene.

"What's really exciting is that there are new drugs -- new inhibitors -- that target these genes. They can put the brakes on these rapidly-dividing cells," said Lynn Schuchter, M.D., Chief of Hematology and Oncology Abramson Cancer Center at the University of Pennsylvania.

In some patients, whose tumors have a broken B-RAF gene, the inhibitors even shrink tumors by 50 percent or more.

"Three days after taking the drug, I wake up on my left-hand side, and I don't have this discomfort in my stomach. I move over to my right, and I don't have it."

Doctor Schuchter says while patients have had tremendous results, eventually, the melanoma cells may become resistant. The next step? Combining the B-RAF inhibitor with other therapies -- and ultimately -- find a cure. Hope keeps Michael Sosnowicz strong. Hope ... and his family.

"I want them to be fighters just like me."

For more information on other series produced by Ivanhoe Broadcast News contact John Cherry at (407) 691-1500, jcherry@ivanhoe.com.

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MEDICAL BREAKTHROUGHS - RESEARCH SUMMARY:

BACKGROUND: Melanoma, the most serious type of skin cancer, develops in the cells that produce melanin -- the pigment that gives your skin its color. Melanoma can also form in your eyes and, rarely, in internal organs, such as your intestines. Melanoma accounts for less than 5 percent of skin cancer cases but a majority of skin cancer deaths. Melanoma is the fifth most common cancer among men and the seventh most common cancer in women. Sometimes, melanoma is found in children and teenagers. The exact cause of all melanoma is not clear, but exposure to ultraviolet (UV) radiation from sunlight or tanning lamps and beds increases your risk of developing the cancer. Other factors, such as your genetic makeup, likely also play a role.
(SOURCE: Mayo Clinic)

STANDARD TREATMENT: People with melanoma may have surgery, chemotherapy, biological therapy, or radiation therapy. Patients may have a combination of treatments. At any stage of disease, people with melanoma may have treatment to control pain and other symptoms of the cancer to relieve the side effects of therapy and to ease emotional and practical problems. This kind of treatment is called symptom management, supportive care, or palliative care.
(SOURCE: Medicinenet.com)

NEW ANSWERS: Scientists from The Institute of Cancer Research (ICR) showed that in human cancer cells and mice, a gene called BRAF -- which is damaged in about half of all skin cancer cases -- triggers a cell signaling pathway that ultimately "blocks the instructions" from a second gene called PDE5A. In healthy cells, PDE5A acts as a brake to stop cell movement. However, in cancer cells, BRAF turns PDE5A's signals off, removing its ability to block cancer spread. By blocking the activity of PDE5A, BRAF drives skin cancer cells to invade new tissues and spread further around the body, converting skin cancer into a more aggressive disease. BRAF is only expressed in 8 percent of cancer but 50 percent of melanomas. BRAF inhibitors like PLX4032 (vemurafenib) inhibited proliferation of tumor cell lines, a mutation found in several human cancers including melanoma. The compound also showed partial or complete tumor regression and improved survival in a dose-dependent manner in preclinical efficacy models in rodents, without associated toxicity. “What’s really exciting is that there are new drugs, new inhibitors that target these genes. They can put the brakes on these rapidly-dividing cells,” Lynn Schuchter, M.D., Chief of Hematology and Oncology at the Abramson Cancer Center at the University of Pennsylvania, told Ivanhoe.
(SOURCE: American Association of Cancer Research)

FOR MORE INFORMATION, PLEASE CONTACT:
University of Pennsylvania Health System
(800) 789-PENN
http://pennmedicine.org/cancer

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THE FOLLOWING IS AN IN-DEPTH INTERVIEW WITH THE DOCTOR FROM THE STORY ABOVE:

Lynn Schuchter, M.D., Chief of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania discusses the advancements in treatments for melanoma, and how BRAF inhibitors and immunotherapy are giving patients a better quality of life for a longer period of time.

Can you briefly discuss melanoma and the novel approach that has been taken by you and your clinic to help the melanoma population?

Dr. Lynn Mara Schuchter: What is really exciting right now is a whole new way of approaching and treating melanoma. Melanoma is a type of skin cancer and it is the most serious one at that. What has been learned over the past few years is that there are specific genes that are mutated and/or abnormal in melanoma, and these mutations are in fact responsible for driving the growth of the cancer. What is really exciting is that there are new drugs which target and inhibit these activated or broken genes. These new inhibitors target these genes, and put the break on these rapidly dividing cells.

Can you discuss some of the recent trials and studies that have give you some insight into this detrimental disease?

Dr. Lynn Mara Schuchter: In about 40 percent of patients who have melanoma, they have a broken BRAF gene, so the gene is activated and mutated. What has been studied is a very selective and potent BRAF inhibitor known as PLX4032, but essentially, it was the first medicine that effectively put the brakes on this target. For patients that have advanced melanoma – that is melanoma that has traveled throughout the body – if the patient’s melanoma has a mutated BRAF gene, the shrinkage rate of their tumor is approximately 50 – 80 percent. This is really unprecedented activity, and what has also been shown is that patients actually live longer as a result of getting this treatment.

How difficult has it been in the past for you to treat melanoma, especially at the advanced stages aforementioned?

Dr. Lynn Mara Schuchter: Patients with stage IV or advanced melanoma, there were really no effective medicines or therapies that prolonged life. When we gave patients treatment, the average shrinkage rate would be in the 5 – 20 percentage and very short lived. So if patients did derive some benefit, the benefit would last about 4 – 8 weeks in most cases. With these new therapies, however, the response/shrinkage rate is ultimately much higher and patients are living on average (stable disease) longer. The progression free survival is 9 months, that is, how long patients go without disease progression which much better than in the past when disease progression occurred in 2-3 months. That number may not sound like a lot –9 months – but it really is a dramatic difference in the way patients are currently being approached and how they are being treated. The other exciting thing about this is that the treatment is a pill; it is very, very easy to take. Patients take this therapy at home, and it doesn’t have the serious side effects and consequences that come with chemotherapy.

Is it a quality of life issue as well?

Dr. Lynn Mara Schuchter: It is a very easy treatment to take. Patients on this regimen take one pill two times daily. There can be some side effects (i.e. skin rash, arthritis), but you don’t see a lot of nausea and vomiting in addition to the hair loss that comes with chemotherapy, so the quality of life with this treatment is so much better in comparison to traditional methods of chemotherapy. This medicine can also cause squamous cell skin cancer, this is the non serious form of skin cancer so patients do need to be closely monitored.

How widespread of an impact could this drug have on the melanoma population?

Dr. Lynn Mara Schuchter: That is a very good question. In the United States, there are approximately 68,000 new patients with melanoma diagnosed each year, and about 7,500 patients with melanoma die each year. For most cases of melanoma (if they are detected early) can be effectively treated with surgery. This new therapy will apply to about 40 - 50 percent of patients with melanoma, because only 40 – 50 percent of patients with melanoma have this BRAF gene, and this treatment is mainly going to be implemented in cases with advanced melanoma. As these therapies get FDA approved and as we further understand the safety and efficacy of it, it will be moved into earlier and earlier stages of the disease. The idea would be that if someone was diagnosed with melanoma and were at risk for recurrence but before it has spread or metastasized, patients may in the future take this therapy to prevent a recurrence. So the next wave is going to be testing this new therapy in earlier and earlier stages of the disease, and really stop the disease from ever getting to the point of being life threatening.

What is it like to see the progression of therapies to treat melanoma having an effect on your patients and allowing them to live a normal quality of life?

Dr. Lynn Mara Schuchter: I have been treating patients with melanoma for almost 25 years, and we now have tears of joy in clinic when we see patients with all of symptoms related to their melanoma (i.e. pain, swelling, shortness of breath), and we have seen some patients within a period of 72 hours actually come off their pain medication . . . so the tumor responses can at times be exceptionally dramatic. The other thing that I have to mention is that while patients are experiencing these benefits and living longer with the aid of these therapies, at some point the melanoma cells become resistant. A major focus of our research now is understanding why melanoma cells become resistant and how we ultimately overcome that resistance. So the focus of newer clinical trials is to combine this novel BRAF inhibitor with other agents to try and prevent resistance, and to try and make patients live longer and eventually cure them of this.

Is that in combination of the immunotherapy that you previously mentioned or is that something separate?

Dr. Lynn Mara Schuchter: Both approaches are being taken. So combining BRAF inhibitors with other targeted therapies – the BRAF inhibitor is an example of a molecularly targeted therapy. What that means is that it is targeting the genes that are broken in a patient’s melanoma. You’ve heard about this concept of personalized medicine, and what we mean by that is we understand the genetic makeup of a patient’s melanoma, and then we match the genetic makeup (the broken genes) with a drug that targets that specific abnormality, so personalized in the sense that really understanding the genetic abnormalities in a patients tumor and giving them the affective targeting agent. The approach now is to build upon the BRAF inhibitor story – to combine those BRAF inhibitors with other agents, and there is a lot of attraction to another pathway that is called PI3 Kinase or combining it with an approach that is called a MEK-inhibitor. So this is really blocking the pathways that are driving these cancer cells, and it really is going to involve a multipronged approach so that we can’t just block one pathway. The cancer cells outwit us. They rely then on yet another pathway, so it is going to involve really blocking multiple pathways and doors in the individual cancer patient.

Can you briefly discuss the other therapy that you are currently investigating?

Dr. Lynn Mara Schuchter: Another approach different from the BRAF inhibitor story is immunotherapy. Immunotherapy is another way to treat melanoma, and the purpose of immunotherapy is to rev up an immune response, to harvest the power of the immune system to recognize melanoma cells and ultimately kill them. One of the new approaches is with a novel drug called ipilimumab (we call it “ipi” for short). What this drug does is take the breaks off the immune system. It allows for a full immune response, and this new therapy became FDA approved in March. This medication is available for patients with advanced melanoma (i.e. stage IV melanoma) and also for patients with advanced stage III melanoma. This treatment is given intravenously, and it definitely revs up the immune system. Recent studies have shown that taking ipilimumab will help shrink melanoma. One of the side effects of ipilimumab is that since it does stimulate the immune system, the immune system can ultimately attack the patient, and this is called an autoimmune complication. When stimulating the immune system, the T cells and other immune activated cell don’t just target cancer, target melanoma, but in addition, target normal organs. So patients are observed immune related adverse reactions. Target organs includes the GI tract, skin, liver, endocrine glands, and the nervous system. Therefore patients are monitored for diarrhea, rash, fatigue, and their blood tests are monitored. They are all manageable, but it involves a team approach to monitoring the patients and making sure that they don’t have too many adverse side effects related to the treatment.

So you think that the FDA will in due course approve ipilimumab by the end of the month? ( was approved)

Dr. Lynn Mara Schuchter: Yes. We think that they will approve ipilimumab by the end of the month.

That has to be exciting when you look at melanoma, and see that it has not had as much progression in therapy in comparison to a multitude of other disease that are easily treatable and curable, right?

Dr. Lynn Mara Schuchter: There are very few drugs that have been approved by the FDA for the treatment of melanoma, so this is really exceptional for patients who have this disease and are losing hope. 2011 turns out to be a remarkable year for patients with melanoma.

In terms of the BRAF inhibitor, what is the time frame for possibly having the drug become FDA approved and moreover beginning to treat individuals with advanced stages of the disease?

Dr. Lynn Mara Schuchter: We are hoping it will approved by the end of the years or perhaps the first quarter of the subsequent year.

So it is a little but further out than the aforementioned ipilimumab in terms of being implemented in the treatment of the melanoma population?( ipi approved, how do you want to handle).

Dr. Lynn Mara Schuchter: Yes.

What are the ongoing trials as well as the upcoming ones that may shed new light on the treatment of this disease?

Dr. Lynn Mara Schuchter: One of the trials is combining the immunotherapy with the BRAF inhibitor. That is one of the upcoming trials. We hope to combine the BRAF inhibitor (plexicon – Genentech drug) with the ipilimumab. That is currently still on the drawing pad right now. There is further interest in combining the BRAF inhibitors with other targeted agents. Other companies are also developing BRAF inhibitors, such as GSK. Their BRAF inhibitor also looks promising. Combination of targeted therapies are currently ongoing. The studies have accrued patients really rapidly, so there are many opportunities for patients who are seeking treatments around the United States. The pace of the study, the pace of the accrual of patients on the clinical trials has really been unprecedented for our field, and it really shows how active these drugs are, and it really shows the importance of why we invest in basic science. The gene BRAF was discovered in 2002, and quickly clinical trials became available. The first drug wasn’t too successful (sorafenib), but then pharmaceutical companies in addition to biotech worked hard to find a more selective and potent BRAF inhibitor that rapidly entered clinical trials. Within a short period of time, phase I, phase II and now the randomized phase III trial has been completed in a very short time frame.

In terms of age range, is this particular study and therapy more suited for a specific population rather than another?

Dr. Lynn Mara Schuchter: Well, melanoma does tend to affect younger age groups than most other cancers, but really we are focusing on patients over the age of 18. Metastatic melanoma in kids is rare. Melanoma though is beginning to become a growing concern in pediatric population, but most people who have advanced melanoma are in their 30-’s and go all of the way up to patients in their 80’s. It is really a wide range adult population.

I know that we cover the BRAF gene specifically, but are there any other genes that are being targeted for this disease?

Dr. Lynn Mara Schuchter: The first step was finding the BRAF gene, which is in about 40 – 50 percent of patients with melanoma but there are other genes that can be mutated in melanoma. A gene known as CKIT (CD117) happens in melanoma that occurs in older people and in heavily sun exposed parts of the body. Furthermore, there is a gene known as NRAS that can become heavily mutated, and we would develop certain drugs that would target those specific genes. So what is really important to understand is that melanoma is not just one disease – it is a group of diseases. It is really imperative that we molecularly characterize each patient’s melanoma. What that means is that you take each patient’s melanoma, and you identify the genes that are abnormal and are driving those cells to grow, and ultimately selecting the drug that is most effective for that particular individual’s disease.

This was not even something on the radar screen when you first started.

Dr. Lynn Mara Schuchter: That is absolutely correct. Understanding the molecular biology has really given us great hope as well as great insight into the disease. It is really a great and optimistic time for all of our patients who are suffering from melanoma.


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