Targeted therapy plus chemotherapy may pack 1-2 punch against melanoma

May 15, 2008

By targeting and disabling a protein frequently found in melanoma tumors, doctors may be able to make the cancer more vulnerable to chemotherapy, according to a new study by researchers in the Duke Comprehensive Cancer Center.

“We tested a compound that can weaken the tumor by targeting a protein expressed on the surface of a melanoma cell. When chemotherapy was applied to the tumor in this weakened state it was much more effective compared to conventional therapy alone,” said Douglas Tyler, M.D., a surgeon at Duke and the Durham Veterans Affairs Medical Center, and senior investigator on this study. “These results are extremely significant because they may help us better treat patients with this deadly condition.”

Although this study was done in laboratory rats, a clinical trial applying the same concept to humans has already begun at four comprehensive cancer centers nationwide, including Duke.

The researchers published their findings from the animal study in the May 15, 2008 issue of the journal Cancer Research. Funding for this study came from the United States Department of Veterans Affairs, the Duke Institute for Genome Sciences & Policy, the Duke Comprehensive Cancer Center and Adherex Technologies, the company developing the compound that was tested in combination with chemotherapy.

After being implanted with melanoma tumors, rats were given a drug known as ADH-1, which makes it difficult for cells to bind properly to one another. The animals were then given one of two types of common chemotherapy drugs, melphalan and temozolomide.

“We found that the response to ADH-1 in combination with melphalan was more dramatic than the response to the drug in combination with temozolomide," Tyler said. "The reason may be that the melphalan was infused directly into the affected area while temozolomide is given systemically.”

The researchers saw a 30-fold reduction in tumor size following treatment with ADH-1 and melphalan chemotherapy compared to chemotherapy alone. Tumor size shrunk about twofold in response to ADH-1 and temozolomide, Tyler said.

“We saw a complete regression of the tumors in the animal model when we used the regional melphalan chemotherapy in combination with ADH-1, which is far better than anything we have seen before with the chemotherapy alone,” Tyler said. “Furthermore, the addition of ADH-1 produced no additional side effects, which is an important consideration in cancer treatment.”

Regional infusion of chemotherapy for melanoma is given under surgical conditions, through the artery and vein in the affected limbs. Melanoma often affects people on their extremities, with a common scenario being a mole that appears on the foot and then spreads up the leg.

“These results clearly demonstrate the effectiveness of combination therapies,” said Christina Augustine, Ph.D., a researcher in Duke’s Department of Surgery and lead investigator on the study. “Used alone the ADH-1 really didn’t confer any significant benefit but in combination with the melphalan chemotherapy, we saw a powerful one-two-punch effect.”

The incidence of malignant melanoma is increasing at a rate faster than any other cancer, with 60,000 new cases expected to be diagnosed this year in the United States. Melanoma that has spread beyond the primary site is rarely curable, and treatment options are limited; even when it is treated, the response rates are typically poor and most people die within six to nine months.

Source: Duke University

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not rated yet May 16, 2008
What Is Targeted Therapy

For the last two decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy. The drugs targeted rapidly dividing cells, including cancer cells and, of course, certain normal cells (cancer cells and healthy cells). Traditional chemotherapy does not have any mechanism to distinguish between them.

In the last few years, 'targeted' therapies are becoming a component of treatment. 'Targeted' therapy is designed to block a specific gene or protein that has a critical role in the survival, growth, invasion, or metatasis of a specific cancer cell. It takes advantage of the biologic differences between cancer cells and healthy cells by 'targeting' faulty genes or proteins that contribute to the growth and development of cancer.

In other words, 'targeted' treatments fight cancer by correcting or modifying defective 'pathways' in a cancer cell. In healthy cells, each 'pathway' is tightly controlled. For instance, healthy cells are allowed to divide into new cells, and damaged cells are destroyed. However, in cancerous cells, certain points in the 'pathway' become disrupted, usually through a genetic mutation (change in form).

Designing "targeted" anticancer drugs begins with identifying the genes or proteins that are specific to the development of cancer and testing whether blocking those genes or proteins gets rid of the cancer. Genetic (molecular) tests are instrumental in accomplishing this task.

However, understanding 'targeted' treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific 'pathways' that involve various genes and proteins in a cell.

Genetic testing examines a single process within the cell or a relatively small number of process. The aim is to tell if there is a theoretical predispostion to drug response. Cell-based testing not only examines for the presence of genes and proteins but also for their 'functionality' (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to 'targeted' drugs).

Genetic testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Genetic tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Genetic tests tell us anything about drug combinations.

Cell-based testing looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy. Sometimes a drug will inhibit the 'target' but not stop the growth of cancer. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

The are many pathways to altered cellular (forest) function, hence all the different 'trees' which correlate in different situations. Improvement can be made by measuring what happens at the end of all processes (the effects on the forest), rather than the status of the individual trees (pathways/mechanisms). You still need to measure the net effect of all processes, not just the individual molecular (gene/protein) 'targets.'

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