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New Drugs for Old Crabs

Published on December 8, 2016

Originating from the Greek “karkinos”, which means crab, cancer, like its crustacean counterpart, pinches unexpectedly and without warning, and once it clings on, it is not easily dislodged. Hippocrates described cancer “with veins stretched on all sides as the animal the crab has its feet”.
We know today that the uncontrolled growth of a single cell causes cancer. This growth is the result of mutations; of changes in the DNA that will affect genes specifically. Those genes generating an unlimited cell growth are part of a powerful genetic circuit, which regulates cell division and death.
The same cell division that allows us to grow, adapt and repair ourselves as living organisms, also enables cancer to grow, adapt and prosper—to live at the expense of our lives.
Therefore, the secret to battling the sea beast is to find ways of preventing those mutations in the cells more likely to be targeted or of eliminating those mutations without compromising the growth of normal cells. Because normal cells so closely resemble cancer cells, combatting cancer is “almost-not quite, but almost-as hard as finding some agent that will dissolve away the left ear, say, and leave the right ear unharmed,” per William Wolgom, a physician and researcher from the early 20th century. Surgery in 1903 at the John Hopkins Hospital by Dr. William Stewart Halstead (known for his drastic surgeries)

The Hunt Is On
In the 1890s, if a tumour was local, confined to an organ or situated in a location from which it could be surgically removed, then there was a chance of recovery. However, crab’s legs have the strange property of growing back after being chopped off. The first breast tumour masses were treated through surgeries that were minimally invasive or not invasive enough. The mass was contoured out and extracted with a scalpel, leaving behind a few invincible cancer cells that wound up taking control back over their surrounding area. When responding to those failures, surgeons of those days did not hesitate long to operate more deeply and remove the whole breast—an efficient procedure for non-invasive tumours, but that only prolonged the inevitable recurrence in more advanced cases. That’s when they decided to go “scrape” around the nearby ganglions and even to remove a few ribs and some muscles and nerves from the shoulder, making some women lose the use of an arm, before they realised that cancer cells could detach from the primary tumour and migrate towards other organs.
Hence, those series of conclusive, inconclusive, and more-or-less radical surgeries gave surgeons a glimpse of the still unknown notions of stages and metastases. The smaller crabs are easy to find and catch, but the bigger ones hide in the sand, safe and out of touch.
With the discovery in the 1900s of X-rays targeting DNA, cells with the highest growth rate in an organism could be killed preferentially without the use of a scalpel. Radiation therapy became available in the early 20th century. With an ever-greater precision, physicians pierced through the outer shell of the tumour, much like the shell of a crustacean, and penetrated deeply to eliminate cancer cells.
A choice between a warm ray or a cold blade—back then, curing cancer followed two principles: removing and destroying the diseased tissue.

The crab’s progression is odd: walking sideways; going forward and back; speeding up and slowing down; stopping and starting up again.

The complex nature of this sea monster drove Sidney Farber, a pediatric pathologist, and the future father of chemotherapy, to seek a more efficient therapeutic alternative. The concept of an anticancer chemotherapy emerged: a chemical agent that could cure cancer, a sort of “penicillin for cancer,” as some pictured it at the time.
In the 1950s, Farber discovered a powerful anticancer chemical agent—a vitamin analogue—and started dreaming of a universal remedy for cancer. Inspired by folic acid—an essential building block of DNA playing a vital role in cell division—, he decided to create an antagonist: a molecule mimicking this natural molecule and blocking its action, like a false key blocking a lock. Consequently, cancer, however aggressive, could be treated with a drug, a chemical.
Once again, the difficulty lied in finding a selective poison, an agile scalpel: sharp enough to kill cancer, but selective enough to save the patient.

A Crab Trap
A long era of chemotherapy began: antifolate, cyclophosphamide, cytarabine, prednisone, asparaginase, adriamycin, thioguanine, vincristine, 6-mercaptopurine, methotrexate. A nearly constant rain of sharp scalpels crashed down on the sea monster and eventually damaged its environment.
The discovery of the first molecules in the 1950s were incidental observations; accidental discoveries of poisons capable of inhibiting the growth of cancer cells. But to develop the ideal cancer drug, one must reason backwards: much like the crustacean, it’s necessary to stop, go back, identify a specific molecular target in the cancer cell, start again, speed up, produce a chemical agent that will tackle that target. Today, thanks to our growing understanding of basic biology, we can target more specifically the genes that prompt cell division and the proliferation of cancer cells (oncogenes) as well as the genes involved in cancer regulation (tumour suppressors). Imatinib, sorafenib, dasatinib, aflibercept, axitinib, trametinib… The scalpel is growing sharper and nimbler.

Inching in, hiding out…

The seafaring creature is sly and blends in its natural environment. Indeed, a cancer cell so closely resembles a normal cell that it integrates seamlessly in the living organism’s environment, which it invades and colonizes, free from any threats.

William Bradley Coley Pioneer bone surgeon William B. Coley, who conducted research works in the 1900s, decades before the first cancer chemotherapies, decided to tackle the creature from a completely different angle. Instead of using a chemical agent to attack the dividing cell directly, he opted for an infectious agent—a bacterium, or a toxin from bacteria (Coley’s toxin)—to stimulate the patient’s own immunological defenses that would, in turn, attack and destroy infected cells. Immunotherapy was born—ingenious and promising, but met with a frosty reception from the scientific community at the time. It would only re-emerge a century later, in the 2000s.

To Arms!
We now know that cancer is not only a disease of the genes, but also of the organism, the tumour environment, and the immune system. The crab finds ways to hide, and cancer cells have the capacity to escape and elude the immune system.
It appears that a new army, with the potential to destroy cancer cells, already resides within us: our own defense structure, the cells of the immune system. The current strategies to use those immune cells against the sea monster consist in either education or activation. “If the immune system does not recognize the tumour as foreign in the organism, it must (…) be trained to identify it as dangerous. If there is an immune response, it will be a question of stimulation, to give the system a dimension to match up its opponent,” explained Vassili Soumelis, physician and immunologist at the Institut Curie, in France.

“Trained to identify the tumour as dangerous”

Every cell in the body is under the strict, almost military supervision of the immune system. The specific characteristics of every cell or antigen are generated by the cell, and then presented for analysis to the immune system. The system will then either identify it as self and there will be no reaction, or it will identify it as foreign and dispatch an army of immune cells to attack the cell in question.
Thus, the secret to fight our seabed creature is to manipulate the immune system, to train it to recognize tumour cells specifically by identifying their individual characteristics or antigens and treating them as foreign entities. To this end, we must explore the depths of the tumour cell to pinpoint its characteristics, its specific tumour antigens…
That is how, hand in claw, we are opening a new chapter in therapies to try to eradicate the sea monster.
“The perfect therapy has not been developed. Most of us believe that it will not involve toxic cytotoxic therapy, which is why we support the kinds of basic investigations that are directed towards more fundamental understanding of tumor biology. But… We must do the best with what we have,” per Bruce Chabner, an American medical oncologist in a letter to Rose Kushner, an American journalist who were particularly interested in the fight against cancer in the second half of the 20th century.
The discovery of the first human tumour antigens recognized by the immune system took place about twenty years ago. However, the translation from concept to clinical application only just started with a handful of clinical trials unearthing exciting exploratory concepts.
Evidence suggests that adaptive immunity leads to clinical benefits in the long term, when combined with cancer treatments such as chemo- and radiation therapy.

Charlotte Girondel
Ph.D. Student in pharmacology
Sylvain Meloche Laboratory
Charlotte seeks to determine if the absence of the protein SEF has an impact on tumour initiation and progression in certain types of cancers. This largely unstudied protein appears to act as much on cell proliferation than on the very first defense system of the body, the innate immune system, making it an interesting therapeutic target.

References:
About surgery

About X-rays

About Sidney Farber and chemotherapy

  • “Sidney Farber (1903-1973).” Journal of Pediatrics (1996).

About William Coley and immunotherapy

About the additional information