Saturday, August 19, 2017

Review of The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee

The Emperor of All Maladies, the Pulitzer Prize winning history of cancer treatment published in 2010, is the kind of book that most people "review" by summarizing, and I am not going to do that.

Cancer is a disease that, sadly, will touch everyone during their lifetimes. It is good to stay up to date with the science. The book mentions two really interesting papers on cancer from the past decade.

The first is "The Hallmarks of Cancer," published in the journal Cell in January 2000 by the cancer researchers Douglas Hanahan and Robert Weinberg. There are six hallmarks:

  • Cancer cells stimulate their own growth (self-sufficiency in growth signals)
  • They resist inhibitory signals that might otherwise stop their growth (insensitivity to anti-growth signals)
  • They resist their programmed cell death (evading apoptosis)
  • They can multiply indefinitely (limitless replicative potential)
  • They stimulate the growth of blood vessels to supply nutrients to tumors (sustained angiogenesis)
  • They invade local tissue and spread to distant sites (tissue invasion and metastasis).
The nutritional supplements and beneficial phytochemicals that we talk about (e.g. Mangan) are often hypothesized to work by inhibiting one or more of the pathways behind these hallmarks.

There is also a 2011 update to hallmarks of cancer, which proposed four new hallmarks: abnormal metabolic pathways, evading the immune system, genome instability, and inflammation.

Abnormal metabolic pathways is interesting because cancer cells may be inefficient at metabolizing ketones, which would support a ketogenic diet as an anti-cancer treatment.

Inflammation hallmark is interesting because if you pay attention you start to see chronic inflammation as a common input in carcinogenesis.

The second paper is Cancer Genome Landscapes, published in 2013. See the summary:
Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of "mountains" (genes altered in a high percentage of tumors) and a much larger number of "hills" (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or "drive" tumorigenesis. A typical tumor contains two to eight of these "driver gene" mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance.
The hallmarks, then, seem to follow as a consequence of these driver genes. From this paper and from Emperor of All Maladies, the prospect of being able to cure all metastatic cancers seems far away. Drugs can interfere with protein function (targeting the growth promotion pathways), but they can't replace the function of defective genes such as those resulting from mutations in the tumor suppressors. The conclusion:
Today,we are in no better position to cure polio or massive myocardial infarctions than we were a thousand years ago. But we can prevent these diseases entirely (vaccines), reduce incidence (dietary changes, statins), or mitigate severity (stents, thrombolytic agents) and thereby make a major impact on morbidity and mortality.

This focus on curing advanced cancers might have been reasonable 50 years ago, when the molecular pathogenesis of cancers was mysterious and when chemotherapeutic agents against advanced cancers were showing promise. But this mindset is no longer acceptable.
Instead, it seems important to figure out how to prevent more cancers via better diet and lifestyle, and to detect tumors earlier so that surgery can remove them before they have metastasized.



CP said...

See also
Happy Accidents: Serendipity in Modern Medical Breakthroughs by Morton A. Meyers

Which discusses the disappointing results of the "War on Cancer".

Anonymous said...

Should we all be taking Metformin? Metformin is a diabetes drug but researchers have found that the people taking the drug also get dramatically fewer cancers. Here is Wired:

What they discovered was striking: The metformin-takers tended to be healthier in all sorts of ways. They lived longer and had fewer cardiovascular events, and in at least some studies they were less likely to suffer from dementia and Alzheimer’s. Most surprising of all, they seemed to get cancer far less frequently—as much as 25 to 40 percent less than diabetics taking two other popular medications. When they did get cancer, they tended to outlive diabetics with cancer who were taking other medications.

As Lewis Cantley, the director of the Cancer Center at Weill Cornell Medicine, once put it, “Metformin may have already saved more people from cancer deaths than any drug in history.” Nobel laureate James Watson (of DNA-structure fame), who takes metformin off-label for cancer prevention, once suggested that the drug appeared to be “our only real clue into the business” of fighting the disease.