By Alice McCarthy

Just three months before Dolores Covati was diagnosed with advanced melanoma‚ she lost her sister-in-law to breast cancer.

“When I was diagnosed‚ I decided that I didn’t want my family to lose somebody else‚” explains the 56-year-old from Whitestone‚ New York. After undergoing surgery and unsuccessful interferon treatments‚ Covati enrolled in a phase III clinical trial at New York University (NYU) Hospital and began treatment with the experimental drug Genasense™ (also known as G3139 or oblimersen)‚ a new drug that targets specific genes to attack cancer cells.

“At the time I was diagnosed‚ my leg was three times larger than normal‚” remembers Covati. “Eventually‚ I was in a wheelchair because I was in too much pain and couldn’t walk. “After meeting with doctors at NYU Hospital‚ Covati knew she wanted to give this therapy a try.

Drugs like Genasense are the result of research gains in understanding how genes work in cancer and other diseases.

“It is now conceivable that our children’s children will know the term ‘Cancer´only as a constellation of stars‚” said former president Bill Clinton on June 26‚ 2000‚ when he announced that a map of the human genome‚ the basic blueprint of human life‚ had been achieved. By February 2001‚ scientists had published detailed information identifying nearly all of the human genes down to their most basic level.

The most encouraging news flowing from these discoveries is that researchers are beginning to understand how these genes are involved in cancer development and suppression. For people living with cancer and other illness‚ this means that research has entered an era where scientists can now probe the information contained in an estimated 30‚000-35‚000 genes to develop effective new treatments‚ new screening methods‚ and even ways to prevent cancer.

“President Clinton’s assessment is not just gene hype‚ but gene hope‚” says Alan E. Guttmacher‚ MD‚ senior clinical advisor to the director‚ National Human Genome Research Institute at the National Institutes of Health‚ Bethesda‚ Maryland. “Certainly cancer will still exist‚ but it will certainly become a lot rarer as our knowledge of the makeup and workings of the human genome expands.”
The concerted effort to unravel the human genetic code‚ or genome‚ began in the late 1980s. The Human Genome Project was then conceived and officially launched in 1990. Research progressed quickly—more quickly than researchers had even dared hoped for—boosted by the entrance of a private company in the late 1990s.

Dr. Guttmacher says that what matters to people living with cancer is that‚ because all cancer begins in cells and is thus genetic‚ this information is already clinically useful.


Genetic Codes and DNA
At the heart of all cells—normal cells and cancer cells alike—is the genetic code made up of DNA that tells every cell of the body when to develop‚ how to grow‚ and even what type of cell to become. Cancer occurs when this genetic code is altered‚ or mutated‚ leading to abnormal cell growth.
“Whether cancer is inherited or not‚ understanding the genetic mechanisms at the root cause of the cancer will lead to much more effective prevention strategies‚ screening‚ and treatments‚” says Dr. Guttmacher.
One of these gene-based treatments‚ antisense drugs‚ works at the genetic level to interrupt in a number of ways the complicated messages and connections that occur in abnormal cell growth. “Antisense is a completely new class of drugs with the potential to be very specific in turning off genes‚” says Branimir I. Sikic‚ MD‚ professor of medicine and director of general clinical research at Stanford University Medical Center‚ Stanford‚ California‚ and a researcher in antisense drug clinical tests.

The DNA contained in genes comprises two interwoven strands bound together by unique molecules called nucleotides. Together‚ these DNA strands‚ one of which is termed “sense” and the other “antisense‚” produce molecules that ultimately create proteins that help maintain normal cell growth and health. For reasons still under investigation‚ abnormal proteins in some people can result in cancer.

Antisense technology acts on the protein pathway. Before the DNA code is translated into a protein‚ a prior step transcribes DNA into messenger RNA (mRNA)‚ which carries the “message” of which proteins to produce. Antisense drugs are small molecules that bind to the mRNA produced by the genes that are suspected of contributing to cancer development. The antisense drugs‚ by binding to the mRNA‚ switch off harmful protein.

Antisense drugs have the potential to be much more selective than traditional cancer therapies‚ binding only to specific cancer cells and avoiding normal cells‚ thus minimizing the toxic side effects common to other cancer treatments.

“While there is still an enormous amount of basic science ahead‚ we’re in a period of great promise now both for people living with cancer and for their relatives‚” says Dr. Guttmacher. “Once we understand the genetic mechanisms of who develops a cancer and who doesn’t‚ we can take steps to help lower risk and treat people uniquely for their type of disease at the genetic level.”

Leading Candidates: Affinitac™ and Genasense
The first antisense drug‚ Vitravene™ (fomivirsen) for treatment of eye damage caused by cytomegalovirus‚ became commercially available in 1998. Other antisense drugs are now reaching advanced stages of testing.
Affinitac (LY900003‚ ISIS 3521)‚ which blocks production of a protein involved in cancer cell growth‚ is now in phase III clinical trials for non—small–cell lung cancer. The trials combine Affinitac with two traditional cancer drugs‚ either carboplatin and paclitaxel or gemcitabine and cisplatin.

In an earlier trial‚ the combination of Affinitac with traditional cancer drugs like Paraplatin® (carboplatin) with Taxol® (paclitaxel)‚ improved survival and slowed tumor progression in people with lung cancer. Affinitac‚ developed by ISIS Pharmaceuticals‚ is now being developed in collaboration with Eli Lilly & Co. Another phase III trial‚ this one in combination with cisplatin and gemcitabine‚ is just beginning in patients with advanced lung cancer.

Genasense‚ the drug used in Covati’s trial‚ works by inactivating the mRNA produced specifically by the bcl-2 gene. The protein created by this mRNA is commonly overproduced in many cancers and interferes with a normal programmed process of cell death called apoptosis‚ an important part of cell maintenance that keeps uncontrolled cell growth in check. The protein also appears to be a key player in contributing to chemotherapy resistance in some cancers.

Genasense is in phase III clinical trials for treatment of melanoma‚ myeloma‚ and chronic lymphocytic leukemia. In late April 2002 the drug and its maker‚ Genta‚ received a huge boost when Aventis Pharmaceuticals‚ Inc.‚ one of the world’s largest drug companies‚ paid for the rights to co–develop and market Genasense. The two companies will now partner in development and licensing of the drug in the United States and Europe.
Covati was encouraged when her tumors were measurably smaller after two to three months of treatment.

“I’m now in complete remission and no longer in a wheelchair‚”she says‚ “and I’m thinking of going back to work.“Side effects were not a significant problem for Covati‚ who experienced flu-like symptoms‚ which were eased with other medicines. Other studies are looking for Genasense’s effectiveness in lung cancer‚ acute myeloid leukemia‚ prostate cancer‚ and mantle cell lymphoma—an aggressive form of non–Hodgkin’s lymphoma.

Ribozymes‚ the Molecular Scissors
Along with antisense drugs‚ ribozyme therapy is another potential treatment strategy exploiting information found in the genes. In 1982‚ researchers at the University of Colorado at Boulder discovered a type of RNA that acts as “molecular scissors.” Called ribozymes‚ they bind to and physically break down mRNA before the information contained in undesirable mRNA sequences can be translated into disease-producing proteins.

“By designing ribozymes that cut the mRNAs that code for the ´bad´ proteins‚ a ribozyme can potentially prevent or cure a disease‚” says Nassim Usman‚ PhD‚ chief scientific officer and vice president of research & development at Ribozyme Pharmaceuticals‚ Inc. “With the recent completion of the sequencing of the human genome‚ the number of potential ribozyme drug targets is enormous.”

Ribozyme Pharmaceuticals‚ Inc. has focused on one such target in creating Angiozyme®‚ which works by interfering with a process called angiogenesis in which tumors develop new blood vessels. Tumors require a very rich blood supply to develop‚ grow‚ and spread. The goal of Angiozyme is to block the tumor from initially establishing the food supply that it needs.
“Because of the specificity of ribozymes‚ we expect to have very low toxicity‚” says Dr. Usman. Since antiangiogenesis will likely be a chronic therapy‚ safety and tolerability will be critical to prove. Human tests with Angiozyme began in 1998; two separate phase II trials on advanced breast and colorectal cancers have now been completed. In earlier tests‚ Angiozyme has been shown to be safe and to have minimal side effects in cancer patients using daily‚ at-home injections for up to 16 months. If current tests prove positive‚ a phase III study will most likely begin in 2003.

Looking forward‚ many researchers believe that antiangiogenic compounds will be most effective in combination with more traditional cytotoxic agents. According to Dr. Usman‚ “We believe that finding the correct setting‚ stage of disease‚ type of tumor‚ and timing of therapy are the major challenges in developing antiangiogenic therapies at this time.”

Promises: Better Prevention‚ Screening‚ and Treatment
“We also need to better understand how these drugs get into cancer cells‚ their effects once they’ve entered cells‚ and why some cancers may be affected by them while others are not‚” says Dr. Sikic. He hopes that changes in the chemical composition of the drugs may eventually allow for more convenient delivery‚ compared to the long infusions that are required with most drugs today.

If history is a teacher‚ cancer researchers are very hopeful that advances like these on the gene front will be rapid and clinically potent. Covati agrees. “I’m one very lucky lady. I can dance with my husband again.”