A Very Brief History of CANCER

From there to here in cancer care...

Cancer has been around as long as life. The incidence of cancer remains true to the cumulative DNA mutations over the eons. The mutations whether heritable (Darwinian) or acquired (Lamarckian) bestow a similar consequence upon the cell; they subvert its function and give it sustainable powers. It is a disease that does not comport itself to utilitarian essentialism. Each cancer is unique in form, structure, behavior and outcome and requires precise understanding of the levers and cogs that hide within the shadows.

Discovery:

Back in the 1600 BC the earliest information cataloged on a papyrus, cancer is chronicled as a malady. Bone specimens from mummies have revealed cancer in the bones as chewed out bone fragments. There are spotty viewpoints in isolated silos for a thousand years. No real cogent hypothesis was offered. The deadly disease was taken at face value and left at that for the remainder of the century. Along came Hippocrates in 460-370 BC who posited the “Humoral Theory.”

Within his theory was the dark, evil “Black bile” the harbinger of carcinos or “karkinos” (cancer). With that theory perched on his mind, he lamented in resignation, “There is no cure.” And in those times, there was none, let alone knowledge of how this “beastly tragedy” where posited subsumed life.

Five centuries later Claudius Galenus “Galen” 131-201 AD influenced by the “Humor Theory” used his anatomic skills and known knowledge of medicine as a physician, philosopher and made further strides into the nature of malignancy through the Hippocratic lens of “Humor.” The pervasive sense of nihilism inversely controlled knowledge and treatment of cancer for almost a century and a half thereafter.

Not until 1775 when Sir Percival Pott deduced that chimney sweeps in London contracted scrotal cancer from the soot, did the cause and effect of environment on cancer become known. For the first time a verifiable concrete causality was bared. Something to point a finger at!

Other notables in the field included Rudolf Virchow 1821-1902 a German polymath who viewed cancer tissue under microscopy to determine that it was “a collection of cells derived from other cells.” and repudiated the Hippocratic "Humoral" view of life and disease. The pace quickened. The knowledge advanced. Yet the fear remained.

In 1902 Theodor Boveri a German zoologist in Munich postulated that the centrosome, an “especial organ of cell division” was required in mitosis (cell division) and that aberrant mitosis was the prelude to cancer. He theorized that special check points in the mitotic cycle when mutated could lead to a genetic predisposition towards a malignancy. We were slowly breaching the firewall. We still had a long way to go.

In 1911 Peyton Rous of Johns Hopkins University in Baltimore, Maryland used a cell free filtrate from a chicken sarcoma to cause cancer in a healthy fowl. This transmission was due to a virus named appropriately as the Rouse Sarcoma Virus. Thus the viral etiology of cancer transmission was brought to fore in the field of cancer medicine. We had progressed from soot to a cell free filtrate (virus) as the central cause of this hard to control tragedy. We were peering at the mechanism for the first time.

Yamagiva and Ichikawa in 1915 used the Percival Pott concept to induce skin cancer in rabbits using coal tar and prove chemical carcinogenesis.  And then in 1964 we added tobacco, another vile substance to the growing list of “evil doers!” Chemicals and Viruses ruled the domain of causality in cancer!

"If everyone is thinking alike, then somebody isn't thinking." George Patton

Cancer medicine was to undergo an exponential increase in knowledge flow after the discovery by Watson and Crick of the DNA helix in 1953. Subsequent hypotheses and experimental thrust in understanding cancer was relegated to the study of genetic dysfunction and its relation to disease, more specifically cancer.

In her book “Natural Obsessions” by Natalie Angier the descriptive evidence of how the Weinberg Labs under the tutelage of Robert A. Weinberg discovered the first human oncogene Ras (a promoter gene causing cancer) and the Retinoblastoma (Rb), a tumor suppressor gene is worth a read. The trials and tribulations of discovery and the dogged pursuit all exemplify the enormous grind required in bringing a hypothesis to reality through series of experimentation and validations. Basic science has to toil over experiments and not be reliant on the dubious distinction of transposed conditionality as employed nowadays by the Frequentists. In 1990 another dedicated scientist, Mary Claire King through diligent work discovered the BRCA I and 2 tumor suppressor genes. BRCA 1 and 2 both involved in initiating cancer via mutation triggering malignancies in Breast, Ovaries, Prostate, among other organs. Another door had opened into the nebulous innards of the cancer cell!

There has been a flurry of activity since in the discovery of various cellular pathways and their cell-surface molecules that could incite mischief in extremely well regulated cell machinery through disruption. This disrupting influence can be over-expressions of pro-proliferation molecules for continuous cell growth or suppression of the anti-proliferation molecules akin to a driver using the accelerator without a brake or releasing the brake in neutral gear on a downhill road. There are many known allosteric feed-back loops within the cells that promote and suppress cell activity as well. These discoveries have now taken biology into the realm of epigenetics (study of genetic control by factors outside of the DNA sequence) where small collaborators called micro-RNA, peptides and other proteins have influential impact on the genetic domain to coax the wayward cell.We had arrived at today!

Surgery:

While these discoveries were taking place some stalwarts in medicine were taking note and deciding how best to treat this devastating malady. Overtime these innovators discarded the Hippocratic and Galen nihilism and opted for surgical removal of the cancer to help life along. In 1878 Thomas Beatson realized that removal of the ovaries resulted in a shrinkage of the breast cancer. Twelve years later,William Halstead of Baltimore, Maryland came up with the idea of Radical mastectomy for breast cancer to achieve the R0 state. This was to be later known  as the Halstead procedure.

In 1928 Charles Huggins came to a similar conclusion in men with prostate cancer, removal of the testicles (orchiectomy) resulted in longevity.

From radical Mastectomy and other highly invasive procedures a refinement of thought occurred. What if we could do more with less surgery to prevent future infirmity and disability to the patient? Those “what ifs” were rewarded with the advent of combined approach of limited surgery and radiation therapy. The 1985-90 data showed equivalent survival for radical mastectomy and partial mastectomy combined with radiation therapy. More would be done to determine between those patients that would need radiation after surgery based on the genetic makeup of the cancer itself. Today OncoType DX gene screening arrays help determine the aggressiveness of breast cancer and treatment can be based on select cases. Others gene arrays exist and are in use for lymphomas and prostate cancer. We are currently grappling with the need for intervention and bearing the costs of caring by invoking concepts of “Lead Time Bias” in an effort to reduce potential harm by limiting “early/over diagnosis.” Newer forms of diagnostic tests arrive at the doctor's doorstep everyday to find and weed out this wretched disease and we as doctors use them all. But the constraints of money seem hell bent on controlling further progress. But that will not hold! After all when there was no money the DNA helix was discovered, smallpox vaccine was created out of cowpox and Penicillin grew out of the mold. I am sure the real creators and innovators will find what is needed to carve out a better destiny for the human race against cancer, independent of the regulatory arm twists. Progress in knowledge and understanding will happen, the scale of which only time will tell..

Radiation Therapy:

Radiation therapy started as a low voltage X-Rays (where “X” stood for unknown quantity) after Wilhelm Conrad Roentgen’s discovery of the x-rays in 1896. From those humble beginnings of large penumbras of low voltage radiation therapy to focused conformal radiation therapy of millions of electron voltage tailored to the tumor via Intensity Modulated Radiation therapy (IMRT) to Intraoperative Radiation Therapy IORT to gated modulations based on respiratory movements to the Stereotactic Radiation therapy (Gamma knife/Cyber-knife), the movement has an accelerated pace to provide the maximum tumor cell kill while sparing the normal cells surrounding the cancer. Proton beam therapy a newer more expensive methodology based on the sharp division of Braggs Peak is geared towards a similar methodology as the IMRT and currently used in certain tertiary centers as the radiation therapy of choice with equivalency in results compared to IMRT.

Chemotherapy:

The field of Oncology is the study of cancer and all relevant treatment modalities that will favor the patient. The tools in the field of Medical Oncology started with the advent of World War I. In 1917 the German Army used Mustard Gas against the enemy. The victims showed an absence of white cells in their blood. The modification of the Mustard Gas as nitrogen mustard was then used as treatment in patients with Hodgkin Disease in 1919.  After the bombing of Nagasaki and Hiroshima, in World War II the victims of the bombing showed a complete bone marrow wipe out. With that information, cancer treatment took another step of using radiation therapy to destroy the bone marrow in cancer cases, specifically Lymphomas and used it for Bone Marrow Transplantation as a method of curing the disease. From adversity grew a serendipitous and successful mode of treatment for an un-treatable disease.

Sydney Farber of Boston, Mass used Aminopterin, (DNA inhibitor that competes with the folate binding site of the tetrahydrofolate reductase enzyme) a precursor to Methotrexate in treatment for Acute Lymphoblastic Leukemia in children and achieved excellent results, as a consequence Methotrexate was then used to treat Choriocarcinoma a cancer in the uterus (womb) with gratifying full remissions.

From single drug therapy, a combination of drugs came into vogue to escalate the remissions in cancer. Slow and steady success followed with incremental improvement in remissions and subsequently in overall survival of the cancer patient with these treatments. In treatment of Malignant Lymphoma (DLCBCL) a four drug regimen of  Cyclophosphamide (Alkylating agent), Doxorubicin (DNA intercalator), Oncovin (a Vinca alkaloid that functions as a mitotic inhibitor) and Prednisone (steroid) (CHOP) was used with great success. Even with further modifications and additions of various other chemical agents to CHOP the cure rate remained fixed around the 50%+ range until the advent of Rituximab. When Rituximab was added to (R-CHOP) there was a significant rise in the complete remission rates and subsequent improvement in survival.

Biologic Response Modifiers:

What is Rituximab?  It is a monoclonal antibody directed against the CD-20 cell surface antigen. Since most lymphoma cells expressed CD-20 on their surface, Rituximab complied, attached itself to the surface and prevented further transmission of signals to the nucleus of the cell to grow. However this was not the first immune modulator by any means, Immune modulators or Biological Response Modifiers had been employed previously. The use of Interferon in melanoma and Chronic Myelogenous Leukemia and Interleukin-2 or IL-2 in both melanoma and Kidney cancer were examples of attempts to modify the immune response against the cancer. Additionally studies utilized programming the Dendritic Cells in the bone marrow to activate the T Killer cells (Lymphocytes) into storming and destroying cancer (prostate) with limited success. Companies such as Dendreon produced a product in that fashion called Provenge that afforded a limited improvement in survival of 4 months to patientwith prostate cancer at a cost of $100,000. Newer attempts at modifying immune behavior is via the Check Point Inhibitors to allow the full scale of immune surveillance unhampered by cancer in throwing another mortar attack against the disease.

Infused with the epistemological experience, both perceived and real, the current focus has gravitated to the Tyrosine Kinases (more on these critters in a different post) as the next targets to control. These are extra and intra-cellular proteins that modify cell behavior through manipulation of the cell signal. Various TK inhibitors include Erbitux (Anti EGFR) and Bevacizumab (Anti VEGF) and Imatinib (Anti  c-Kit or Stem cell Growth Receptor) are in use today and more are in the pipeline of the various biotechnology companies.

The idea is to starve the flow of information (Anti EGFR) or flow of nourishment (Anti VEGF) and now possibly manipulate the epigenetics via the override of the microRNAs to calm or speed-up the genetics into forcing the cell into submission.

The next few years will be a bounty of ideas and actions against Hippocrates’ carcinos. Stay tuned...

(There are many other notables that have meant so much in the field of cancer, unfortunately space does not permit for the historical reference to each).

References:

1.       Sara Gandini Tobacco smoking and cancer: A meta-analysis Epidemiology: International Journal of cancer http://onlinelibrary.wiley.com/doi/10.1002/ijc.23033/full

      

      Galen:
       http://www.nlm.nih.gov/hmd/greek/greek_galen.html

      Sir Percival Pott:
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1037746/

      

      Rudolf Virchow:
      http://www.science-of-aging.com/timelines/virchow-pathology-cell-formation.php

      Theodor Boveri:
       http://jcs.biologists.org/content/121/Supplement_1/1.long

      Peyton Rous:
      http://www.nobelprize.org/nobel_prizes/medicine/laureates/1966/rous-bio.html

      Wilhelm Conrad Roentgen:
      http://www.nobelprize.org/nobel_prizes/physics/laureates/1901/rontgen-bio.html

      Sydney Farber:
      http://www.learntoquestion.com/seevak/groups/2007/sites/farber/bio.html