TARGET ACQUIRED
The telephone rings, and Dr. Erlinda Gordon, a Filipino-American scientist based in Los Angeles, California, rouses from sleep to answer it. It is a few minutes past four in the morning. The call is from Manila. Mr. Florante Dionisio introduces himself and courteously gives the reason for his call: "Doctor, please help my wife." Florante's wife has pancreatic cancer and, despite treatment, her cancer has advanced to stage IV-B.
His appeal triggers a series of events that has led to the first human trials for a novel cancer treatment in the Philippines.
The treatment, dubbed as Rexin-G, was developed by a California-based tandem of biochemist-molecular biologist and pediatric hematologist-oncologist. Rexin-G stands for Retroviral Expression Vectors Bearing Inhibitory Genes, and combines a targeted vector system with a proprietary mutant-cell-control gene (anticancer gene).
Killer gene
Although the engineering and development for genetic-therapy protocols for cancers started way before that of Rexin-G, most studies have faced a dead end. Classically, gene therapy for cancer works through two basic strategies: immunizing the body to fight the cancer or introducing vectors (or vehicles) to deliver weapons--a drug or a mutated gene that will sabotage the cancer cell's replication machine--that can fight the cancer. Scientists have already mapped out a lot of the cancer cell's structures for perpetual growth, but an efficient delivery method to counter these mechanisms was still wanting. Designing a targeting device for a vector to home in on the cancer cells seemed simple on paper. Although the results for this possible delivery method looked good in the petri dish, the outcome could not be operatively replicated in studies carried out in animals.
This prompted two scientists, Drs. Erlinda Gordon and Frederick Hall, to pursue a road less traveled. Orthodox studies on designing a vector were geared to being able to recognize the cancer cells themselves or cell-specific targeting. Skewing the perspective a bit, Gordon and Hall developed a plan that would allow a vector to recognize the properties of a diseased cancerous tissue.
The tandem, who cofounded Epeius Biotechnologies, referred to this as a "pathotropic" Targeted Delivery System (TDS). The vectors were equipped with a homing device that would recognize and steadily approach the disease or cancer. Specifically, the vectors exhibit tropism to damage found in cancer tissue: tumor invasion, blood-vessel formation by tumor cells, and even the body's own attempt to wall off the tumor. Once the vector was in the body and found its target, it would then disarm the "cancer-killing" gene.
Rexin-G vector's "cancer-killing" gene is a mutant form of the cyclin G1 gene, first isolated in 1994 and was considered as one of the primary factors in the development of many cancers. The mutant form was reversed from its original form so that instead of promoting growth, it promoted cell death. It turns out that this exerted effect not only on the tumor cells themselves, but also on the growth of their blood supply, an important component for a tumor's survival.
To test the TDS, preclinical studies were made to determine its efficacy and safety on laboratory animals, starting with mice, then rats, then pigs. Results were extremely encouraging. The vector cells were "smart" enough to home in on the cancer cells, arresting their growth and causing a decrease in the size of the tumor. There was also evidence of safety: no suppression of the bone marrow and no alteration in liver and kidney functions.
First in the Philippines
In 2002, Rexin-G was approved by the United States Food and Drug
Administration for phase-I/II clinical trials for metastatic colon cancer.
But the first clinical trial was conducted in the Philippines
with three patients that included Roseann Dionisio, Florante’s wife.
Florante had learned about the opening of a clinical trial on Rexin-G in Los
Angeles and hoped that his wife might be able to participate, thus his
fateful phone call to Gordon. At the time he made the call, his wife’s
pancreatic cancer was in stage IV-B. Roseann had undergone surgery and
chemotherapy, only to receive news that the tumor had recurred.
Following his call, Hall and Gordon made representations with the Bureau of
Food and Drugs (BFAD) to begin compassionate-use clinical trial in Manila. A
month after Florante first spoke with Gordon, the BFAD gave approval for
compassionate use of Rexin-G in clinical trials for end-stage pancreatic
cancer. Thus, on February 14, 2003, the first human trial for Rexin-G began
in Manila under the supervision of Drs. Gerardo Cornelio and Conrado Lorenzo
III.
Results of this first clinical experience with Rexin-G were published in the
International Journal of Oncology in 2004. Completed in 2003 and authored by
Gordon and Hall, along with Cornelio and Lorenzo, the article documented the
results of the treatment with Rexin-G on three end-stage pancreatic-cancer
patients. As if amplifying the effects seen in the preclinical studies in
animals, the results made the investigators very hopeful. All three patients
showed initial decrease in tumor size followed by stabilization. The first
experienced 33- to 62-percent regression of metastatic lymphadenopathy while
the second had a 47-percent reduction in the primary tumor. In the third
trial participant, the primary tumor shrank by 30 percent.
No dose-limiting side effects or toxicity was encountered, a
sign that possibly more vector can be given to produce more effect. The
classical side effects of chemotherapy were not experienced by the
patients—-no nausea or vomiting, no diarrhea, no hair loss, no bone-marrow
suppression, no damage to the liver or kidney. All three patients also
reported a feeling of well-being, suggesting that treatment with Rexin-G may
improve the quality of life of cancer patients, something that most, if not
all, have lost, the study said.
“Although the number of patients studied [was] small, the
results are encouraging as the median survival of patients with stage-IV
pancreatic cancer is only three to six months in spite of aggressive
chemotherapy,” the study concluded.
More trials
needed
The development of Rexin-G has spanned a decade, along with
it the formation of Epeius Biotechnologies and overcoming various obstacles,
and the forging of innumerable human connections. Clinical studies for Rexin-G
are ongoing, and to say that it may represent a “cure” for cancer is at best
premature. Rightly so, the investigators are cautious, stressing that more
data and numbers have to be accumulated so that an objective conclusion can
be made regarding the safety and efficacy of Rexin-G in the treatment of
solid tumors.
But the initial findings have triggered not just hope
but a series of more trials.
In November, Epeius Biotechnologies starts another clinical
trial in the Philippines, this time using Rexin-G with the cancer vaccine
Reximmune-C. The company is currently harnessing more funds to be able to
produce larger amounts of the vector to treat a bigger population with the
hope of integrating gene therapy into standard cancer-treatment protocols in
the future. Other clinical trials have also been established in the US. In
July, the Mayo Clinic Cancer Center began recruiting 24 patients for its
trial.
Meanwhile, the FDA has approved Rexin-G as an orphan
drug, the first gene-therapy product to gain the designation for pancreatic
cancer.
The minds of Epeius
Named after the mythological Greek who designed the great Trojan horse, Epeius Biotechnologies has lived up its name with the development of Rexin-G. Now in the early stages of clinical trials, Rexin-G is a novel cancer drug that has the ability to destroy the enemy much like the Trojan horse--quite unknowingly and with no side effects. Its unique pathotropic Target Delivery System has been patented by Epeius Biotechnologies founder and chief executive officer, Dr. Frederick Lewis Hall.
Hall is a biophysicist and physiologist with a long history of working with cancer. He started with the simple models of cancer and then moved on to work with tumor promoters under a program of the North Atlantic Treaty Organization (NATO) in Dundee, Scotland. Further research led him to further studies with cell-cycle-control enzymes that, in turn, allowed him to map out the gene for cyclin G1, the knockout or mutated version of which is now deployed in Rexin-G. A staunch scientist turned entrepreneur, Hall is now committed full time to ensure that the company's brainchild will reach its intended beneficiaries--cancer patients hoping for a cure.
Says Hall of their discovery: "I soon learned that this targeting technology was highly coveted, and that neither academic institutions nor pharmaceutical companies could be trusted to act with the degree of integrity needed to develop a technology that was disruptive in terms
of their medical authority and cash flow. In this manner, Dr. Erlinda Gordon and I stood pretty much alone for quite some time as champions of a better medicine for the stricken. That is why the Philippine oncologists (Gerry and Gary) deserve so much credit for their pioneering efforts and for their participation in the most critical and important stages of [Rexin-G's] development. Eventually, the technology will be safely in the hands of the physicians of the future, and they won't need us anymore."
Working directly with cancer patients is Hall's colleague, Filipino-American Erlinda Gordon. Considered by her Epeius cofounder as the "anointed one," her passion and vision as a pediatric hematologist-oncologist has helped focus the company's energies.
Gordon affectionately shares the story of her own inspiration, that of a 15-year-old boy with osteosarcoma or cancer of the bone. She tells of the battle he had to fight and eventually lost, but with one unknowing victory speared by his simple and overwhelming request--"find a cure."
Gordon has devoted her life to finding a cure for cancer, and now with ongoing clinical trials for Rexin-G, she is starting to reap the returns. Spearheading the trials with Filipino oncologists, she shares that she is greatly hopeful of the future for cancer patients. But the road was not always easy and there are still obstacles to overcome, mainly financial in nature.
She is currently vice president for operations and medical affairs of Epeius Biotechnologies and has also taken the task of searching for commercial philanthropists to join in their cause.
Local pioneers
When the BFAD approved in 2002 the compassionate use of Rexin-G for a clinical trial on end-stage pancreatic cancer, Dr. Gerardo Cornelio became the natural choice to supervise the trial. He was Roseann Dionisio's oncologist, practicing at the University of the Philippines-Philippine General Hospital, Asian Hospital and Medical Center (AHMC), and San Juan De Dios Hospital.
Armed with a sword of compassion and the shield of a scientist's skepticism, Cornelio was able to bring to reality the first human experience for Rexin-G. He was eventually joined by Dr. Conrado Lorenzo, head of medical oncology at the AHMC, as the administration of Rexin-G evolved into a full-fledged clinical trial.
When asked about the treatment's possibilities, both stressed that extreme caution has to be taken every step of the way. Although initial results looked promising, more studies are needed to validate them.
Both oncologists are hopeful with the trials for Rexin-G. Lorenzo says that with the local implementation of the clinical-trial protocol here in the Philippines, the careful and exact execution has led other institutions in the US to follow suit. He considers this the real merit of their involvement with Rexin-G.
Credit also goes to the first cancer patients who had the courage to tread uncharted waters. Their hope goes beyond curing themselves, and their aspiration extends to other patients who may, in the future, be saved.
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