San Diego's Ocean Beach

Sidney Kimmel Cancer Center

Scientists Protect Against Internal Terrorists

March, 2004 La Jolla Light
By Jim Kelly

Rising like promises from the valley edge of the Torrey Pines plateau are two buildings, one black and one white. Inside these buildings, brain trusts of scientists are engaged in a war on terrorism.

The terrorists come in many forms but they all have one name, cancer.

This war is being waged by scientists from the Sidney Kimmel Cancer Center (SKCC).

Affiliated with Sharp HealthCare, the Sidney Kimmel Cancer Center has accomplished so many breakthroughs in medical science in its 13 years of existence, seven for-profit corporations have been spun off to bring their discoveries to the suffering public.

Avoiding harming normal tissue

The commanding general in this conflict is Albert Deisseroth, M.D., Ph.D., president and CEO of SKCC. "Most cancer treatments in the past were based on therapy that was destructive," Deisseroth said in a recent interview with The Light.

"Cut it out, burn it with radiation or administer intravenous or oral toxins that would, not only kill the cancer cells but would also damage normal tissue."

What SKCC is trying to do is to distinguish what is different about cancer tissue. "Knowing how it is different is very important if you are thinking of targeting it with therapy.

"If we can identify the signature of cancer cells we can target it with a guidance system that avoids normal tissue," Deisseroth said.

Deisseroth and his team of scientists are concentrating on four areas of research, vascular targeting (cutting off the blood supply of a tumor), cancer cell biology, genomics (studying the genetic material of an organism) and immunotherapeutic targeting.

According to Per Borgstrom, Ph.D., a researcher in vascular targeting working in the instituteís black building, the potential treatment being developed would be helpful with cancers when they metastasize (form secondary tumors and spread throughout the body).

"Through genetic identification we can find blood vessels feeding very small tumors," Borgstrom said. "Then we can target these blood vessels and kill them."

Another area of targeting, proteomics, is being done by Dr. Jan Schnitzer, scientific director of SKCC. With his boyish appeal and a easy good nature, Schnitzer looks like he could be playing in an over-the-line tournament.

But what Schnitzer is doing is not a game. Using techniques newly developed in his lab at SKCC to map the proteins at the surface of blood vessels in tumors, he is able to discover new targets that facilitate rapid delivery of drugs directly to tumors which can vastly decrease the dosage needed in therapy.

"In traditional chemotherapy, small toxic molecules go into the circulation system and, because they are small, they are able to get access throughout the body. That leads to well-known and unwanted toxicity.

Through its effect on highly proliferating cells, chemotherapy has the desired greater toxic effect on tumor cells but unfortunately at the price of some normal cells, like in the skin and gut, that also divide rapidly.

This creates a small therapeutic window of toxicity that is pretty crude and rude to the patient."

Cancer's Holy Grail

From these obvious therapeutic shortcomings, a new idea developed that envisioned direct targeting of toxic agents to the tumor cells to create better therapies beyond typical chemotherapeutic agents. This "magic bullet" concept has long been a Holy Grail in medicine's crusade against cancer for almost a century.

With the advent of new biotechnology in the 1970s to make antibodies (large proteins normally made by the body to attack infective agents), a means to target tumor cells specifically became possible.

But as is usually the case in the scientific discovery process, the huge wave of initial enthusiasm became tempered over the next two decades by unforeseen realities and barriers to success.

Antibodies when injected into the blood have a hard time getting inside the tumors. Until recently it was also thought that because all cancer cells even within a single tumor are not alike, no one treatment was believed possible.

Work in Dr. Schnitzerís lab may revive the magic bullet strategy but in a new direction not originally imagined. Like any normal organ of the body, tumors require blood vessels for their growth.

Blood vessels are lined with endothelial cells that form a barrier prevented drugs such as antibodies to reach the intended target for destruction, namely the cancer cell inside the tumor.

For over a decade, Schnitzer has been working on ways not only to target and destroy the blood vessels of tumors but perhaps more importantly also to delivery drugs to cancer cells that lie on the other side of the endothelial cell barrier.

Because these tumors are so hard to get to, past antibody-toxins and even chemotherapies have less than one percent effectiveness.

In other words, more than 99 percent of the toxin does not enter into the tumor but rather circulates throughout the rest of the body to cause the patient to suffer greatly.

But instead of targeting the tumor cell surface as envisaged for the original "magic bullet", Schnitzer's lab has been working on targeting the surface of the endothelial cells.

"We're talking about changing the bullís eye," Schnitzer said. By doing this, his researchers have been able to develop antibodies specifically coded to reach certain endothelial cells increasing the amount of toxin reaching the cancer cell by more than 100-fold.

His lab has discovered a new pathway mediated by special endothelial vesicles called caveolae (means "little caves") to get antibodies through the blood vessel wall to reach the insides of the tumors.

According to Schnitzer, "Tissue penetration across the endothelial barrier is critical for drug delivery and more effective anti-cancer treatments."

Designer drugs

It appears to be possible that a "designer drug" can be developed to work on most types of solid tumors. In addition to this procedure's accuracy in targeting tumors, it is fast-acting. Within 60 seconds of introducing the drug the targeted area is being reached. The efficiency and speed of "changing the bullís eye" keeps the rest of the body from being adversely affected by toxins.

This break-through in cancer research adheres to one of Deisseroth's main principles of destroying the cancer without harming the patient.

Because of Schnitzer's work, a much smaller dose of toxic agent can be administered and previous drugs, discarded because they were considered too deadly at the high doses required, can be re-introduced into future treatment programs.

Next door, in the white building, Deisserothís lab has come up with equally impressive results. In a report released this week in the prestigious "Proceedings of the National Academy of Sciences," SKCC announced a new virus-based vaccine for cancer.

"The vaccine is based on the principal that a virus is one of the best ways to activate the cells of the immune response against cancer cells," explained Deisseroth.

By using a safely-modified cold virus developed by the Deisseroth lab at SKCC called an adenovirus, the team, consisting of Lixin Zhang, Yucheng Tang, Hakan Akbulut, Daniel Zelterman, Phyllis-Jean Linton and Albert B. Deisseroth, has found they can direct the attention of the immune defense system against a marker.

This marker is present at high levels on cancers of the breast, ovary, lung, colon and prostate.

The immune system normally ignores cancer cells because they have the same surface properties as normal cells and immunotherapists have long been challenged to find a way to alert the body to the presence of these dangerous growths.

However, after two injections of the adenovirus Deisserothís lab has created, the sentinel cells of the immune response, the dendritic cells, are alerted so they can recruit the "effector" cells of the immune system to attack and kill the cancer cells.

This adenovirus, referred to as a "vector," has been effective in activating resistance to the growth of cancer cells lasting up to a year.

Although it was created as a prophylactic against cancer, the vaccine has been injected into test animals with an established growth of cancer cells and their tumors have been suppressed.

It has also been possible to transfer the resistance to these cancer cells by injecting spleen cells from one test animal to another.

In addition to making available a vaccine for protection against cancer, the vector might also be of value in the treatment of cancers that recur after surgery and are unresponsive to standard treatments of chemotherapy and hormonal therapy.

Happy scientists

The curious thing about SKCC is not its level of success against cancer, but its ability to attract so many world-class scientists. Jay Jeffcoat, senior vice president for community, public and governmental relations said it was more than the La Jolla weather.

"The center provides a place where scientists are free to pursue pure research," he explained. "They also can experience an immediate application of their work."

To underline his belief, Jeffcoat pointed out a recent finding by one of the centerís scientists, Michael McClelland. McClellandís team unraveled the genetic code of a virulent Salmonella that causes food poisoning.

His research is, hopefully, the first step in developing a vaccine effective enough to help doctors eradicate Salmonella infection worldwide.

"Because of the centerís and Dr. Deisserothís attitudes toward pure research, the work to unravel this code was not just permitted, it was encouraged, even though it was outside the strict definition of cancer research." Jeffcoat said.

Deisseroth echoed Jeffcoat's feelings about SKCC. "All scientists want to feel their lives have been valuable to other people," he said. "Researchers who come here can see a transition from discovery of knowledge into treatment and therapy."

The future for SKCC seems as bright as its past. Through a generous grant from Sidney Kimmel, two parcels of land above the existing buildings have been purchased and new research facilities are in the planning stages.

But SKCC still needs the financial assistance of the worldwide community it serves in order to expand. According to Deisseroth, cancer is the leading consumer of the healthcare dollar and the scientists at SKCC have a moral obligation to fight it.

In the 2002 Annual Report for SKCC he wrote, "If we work together, the result will be the most precious gift of allóthe gift of life."

For more information, go to Sidney Kimmel Cancer Center.