Evolution of Cancer Research

by Rashmi Kumar

This year marks the 100th anniversary of the American Cancer Society. With a century of recognized fighting against cancer, it is only fitting that we reminisce about the strides humanity has made against a disease that has posed as both a catalyst and conundrum in medicine. From brute force chemotherapy to the period of cell signaling to the dawn of immunotherapy, oncology (the study of cancer) can be traced through various eras. The scientific perspective on cancer has morphed throughout the years and the evolution of cancer therapy has been remarkable.

In the Ancient World, Celsus and Galen—two famous medical authorities—labeled cancer as an incurable disease. Before the invention of microscopy, the origin of cancer and its pathology was shrouded in mystery. The first phase of cancer therapy was characterized by “brute force” treatments based on basic physical observations and experiments. “Humors” were extracted and blood was leeched to quench the cancer, and tumors were excised by surgical techniques. Surprisingly, this philosophy of utilizing physical observations to propel cancer therapy serendipitously led to the discovery of the first chemotherapeutic drug: mustine. Also known as nitrogen mustard, mustine is a chemical warfare agent used extensively during the World War I era. In 1917, Edward Krumbhaar, M.D., from the University of Pennsylvania, was sent to France as a medical officer in the American Expeditionary Forces. He conducted autopsies of soldiers exposed to mustard gas and was the first to publish the remarkable leukopenic effects of nitrogen mustard on victims in his book “Blood and Bone Marrow in Mustard Gas Poisoning” in 1919. Soldiers exposed to this chemical had severely reduced numbers of circulating white blood cells.

In 1941, pharmacologists Alfred Gilman, M.D., Ph.D., and Louis Goodman, M.D., were determining the toxicity levels of mustard gas in white rabbits. They, like Krumbhaar, saw highly reduced numbers of white blood cells. If such an agent could be used to reduce the numbers of cancerous white blood cells, the patient had a chance at survival. In their quest to find an antidote for mustard gas poisoning, they had inadvertently stumbled upon the anti-cancer therapeutic potential of nitrogen mustard. The discovery of mustine was the gateway to a new era of cancer therapy.

Until chemotherapy, surgical and radiation techniques could only target solid mass tumors. Additionally, patients had a high chance of survival only if the tumors were small enough to be isolated and removed completely. The scientific approach to cancer therapy changed course; the new focus was on the discovery of new chemical compounds that could target actively dividing cells.

Chemotherapy was valuable in that it could be used in combination with surgery and radiation with great efficiency, thereby decreasing the chances of tumor regrowth. With chemotherapy, cancers that metastasized (traveled to different organs) and blood cancers such as leukemia or lymphoma could be cured. Unfortunately, chemotherapy affected non- cancerous cells as well, prompting the need to create drugs that could specifically target numerous cancer cell populations. In short, oncologists were hoping to find out what characteristics of cancer cells could be exploited for treatment. One miracle drug that arrived during this era of cancer research was Imatinib (or Gleevec). The discovery of Imatinib allows us to take a look into the minds of physicians and researchers during this exciting time.

Officially approved by the FDA in 2001, Imatinib was discovered by Brian Druker, M.D., at the Oregon Health and Science University. Imatinib worked because of one simple idea: it proposed a lock and key model of drug therapy. Imatinib is an inhibitor of a receptor that is overexpressed in cancer cells and prevents constant activation of the receptor by binding to it. It effectively reduces the uncontrolled growth of cancer cells. Imatinib was one of the first drugs that took a characteristic unique to cancer cells and applied it to drug innovation.

While cancer therapy has evolved continuously over the past century, the last decade in oncology has been one of the most innovative. Society is now at the cusp of a new era of cancer therapy that revolves around cancer vaccines. The current phase of cancer therapy taps into the potential of the human immune system and hopes to use our body’s defense mechanisms to identify cancer cells that have previously gone undetected. Interestingly, our very own university has been at the forefront of propelling research focused on cancer vaccines. The research of Pitt Immunologist Olivera Finn, Ph.D., on the colon cancer vaccine holds special relevance in this path-breaking topic.

Finn, a recipient of the American Cancer Society Faculty Award, shared her thoughts on the evolution of cancer research through the decades. For her, the modern shift in understanding cancer came from realizing its impact on the immune system. “You cannot treat cancer as though it is in a petri dish,” says Dr. Finn. “You must think of the host, you must think of the indelible changes that occur in the immune system as a result of this disease.” It is this type of novel thinking that enables her research to introduce a level of specificity to cancer therapy never seen before. Her vaccine is constructed around a protein synthesized by the colon cancer cells. The idea is that if the immune system could be trained to mount a response against this protein then, in principle, they would also attack the cancer cells that secrete this protein. Finn’s vaccine is currently in small Phase I and II clinical trials and shows promise.

Out of the initial 39 people that were administered this vaccine, 17 showed a strong immune response with specificity for the protein. The beauty of our adaptive immune system and cancer vaccines is that they can be highly specific. This approach is different from chemotherapy in that normal body cells would not be targeted by our immune cells. The major advantage is that patients can be administered the vaccine in the pre-malignant stage, before the cells become cancerous. “The whole point of this is to reset the host, and not to focus killing the cancer,” says Finn. If trained to do so, our immune cells will take care of the latter job with ease.

The past century has been explosive for the field of medical oncology. Our understanding of cancer has grown and with it our ability to treat it. No longer is cancer viewed as an incurable disease. Survivorship rate is growing and with it comes knowledge of long-term effects of treatment, allowing us to further improve therapies. From mustine to Imatinib to cancer vaccines, we have traveled far. Hopefully one day all types of cancer will be viewed as curable and not life threatening. However, Finn’s concluding remark during our interview is indeed remarkable: “None of this is necessary, if we focus on prevention.” Until then, we can help by contributing to cancer research, awareness and prevention. Start by getting involved with Relay for Life, contact the local chapter of the Leukemia and Lymphoma Society, and the next time you think about cancer, think about humanity’s progress.