The Cancer Chronicles (37 page)

1.
neatly described by two scientists:
D. Hanahan and R. A. Weinberg, “The Hallmarks of Cancer,”
Cell
100, no. 1 (January 7, 2000): 57–70. [
http://www.ncbi.nlm.nih.gov/pubmed/10647931
]

2.
The idea … goes back decades:
C. O. Nordling, “A New Theory on the Cancer-inducing Mechanism,”
British Journal of Cancer
7, no. 1 (March 1953): 68–72. [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2007872
] Nordling argued that the need for multiple mutations explains why cancer becomes increasingly frequent with age: “If two mutations were required, the frequency of cancer should increase in direct proportion to age.…If three mutations were required, a cancer frequency proportional to the second power of age might be expected, with four mutations to the third power of age, and so on.”
Peter Nowell is often given credit for the first clear description of the idea of cancer as a Darwinian process in “The Clonal Evolution of Tumor Cell Populations,”
Science
194, no. 4260 (October 1, 1976): 23–28. [
http://www.sciencemag.org/content/194/4260/23.abstract
] The theory was put on solid footing with landmark experiments on colorectal cancer. See
Bert Vogelstein et al., “Genetic Alterations During Colorectal-tumor Development,”
New England Journal of Medicine
319, no. 9 (September 1, 1988): 525–32. [
http://www.ncbi.nlm.nih.gov/pubmed/2841597
]

3.
“For decades now”:
Hanahan and Weinberg, “The Hallmarks of Cancer” (italics added).

4.
don’t necessarily have to occur through mutations:
The seminal paper on epigenetics is Andrew P. Feinberg and Bert Vogelstein, “Hypomethylation Distinguishes Genes of Some Human Cancers from Their Normal Counterparts,”
Nature
301, no. 5895 (January 6, 1983): 89–92. [
http://www.nature.com/nature/journal/v301/n5895/abs/301089a0.html
] For a historical overview see Andrew P. Feinberg and Benjamin Tycko, “The History of Cancer Epigenetics,”
Nature Reviews Cancer
4, no. 2 (February 2004): 143–53. [
http://www.ncbi.nlm.nih.gov/pubmed/14732866
] Epigenetic changes in germ cells—sperm or eggs—might even be passed from parent to child, though the significance of that is uncertain.

5.
found to be mutated in different cancers:
Päivi Peltomäki, “Mutations and Epimutations in the Origin of Cancer,”
Experimental Cell Research
318, no. 4 (February 15, 2012): 299–310. [
http://www.ncbi.nlm.nih.gov/pubmed/22182599
]

6.
proposed that cancer actually begins with epigenetic disruptions:
Andrew P. Feinberg, Rolf Ohlsson, and Steven Henikoff, “The Epigenetic Progenitor Origin of Human Cancer,”
Nature Reviews Genetics
7, no. 1 (January 2006): 21–33. [
http://www.ncbi.nlm.nih.gov/pubmed/14732866
]

7.
a contentious idea called the cancer stem cell theory:
Piyush B. Gupta, Christine L. Chaffer, and Robert A. Weinberg, “Cancer Stem Cells: Mirage or Reality?”
Nature Medicine
15, no. 9 (2009): 1010–12; [
http://www.nature.com/nm/journal/v15/n9/full/nm0909-1010.html
] Jerry M. Adams and Andreas Strasser, “Is Tumor Growth Sustained by Rare Cancer Stem Cells or Dominant Clones?”
Cancer Research
68, no. 11 (June 1, 2008): 4018–21; [
http://cancerres.aacrjournals.org/content/68/11/4018.abstract
]
and Peter Dirks, “Cancer Stem Cells: Invitation to a Second Round,”
Nature
466, no. 7302 (July 1, 2010): 40–41. [
http://www.nature.com/nature/journal/v466/n7302/full/466040a.html
] The basic idea was suggested as early as 1937 (J. Furth and M. C. Kahn, “The Transmission of Leukaemia of Mice with a Single Cell,”
American Journal of Cancer 31
[1937]: 276–82), and cancer stem cells were identified in a blood cancer by Dominique Bonnet and John E. Dick: “Human Acute Myeloid Leukemia Is Organized as a Hierarchy That Originates from a Primitive Hematopoietic Cell,”
Nature Medicine
3, no. 7 (July 1, 1997): 730–37. [
http://www.nature.com/nm/journal/v3/n7/abs/nm0797-730.html
]

8.
the more confusing it seemed:
For a taste of the controversy see John E. Dick, “Looking Ahead in Cancer Stem Cell Research,”
Nature Biotechnology
27, no. 1 (January 2009): 44–46; [
http://www.nature.com/nbt/journal/v27/n1/full/nbt0109-44.html
] Elsa Quintana et al., “Efficient Tumour Formation by Single Human Melanoma Cells,”
Nature
456, no. 7222 (December 4, 2008): 593–98 [
http://www.nature.com/nature/journal/v456/n7222/abs/nature07567.html
]; Priscilla N. Kelly et al., “Tumor Growth Need Not Be Driven by Rare Cancer Stem Cells,”
Science
317, no. 5836 (July 20, 2007): 337 [
http://www.sciencemag.org/content/317/5836/337.abstract
]; Richard P. Hill, “Identifying Cancer Stem Cells in Solid Tumors: Case Not Proven,”
Cancer Research
66, no. 4 (February 15, 2006): 1891–96 [
http://cancerres.aacrjournals.org/content/66/4/1891.abstract
]; and Scott E. Kern and Darryl Shibata, “The Fuzzy Math of Solid Tumor Stem Cells: A Perspective,”
Cancer Research
67, no. 19 (October 1, 2007): 8985–88. [
http://www.ncbi.nlm.nih.gov/pubmed/17908998
]

9.
shed their identity and reverted:
One hypothesis is that they would make the transformation through the epithelial-mensenchymal transformation, which is discussed in chapter 6 of this book.

10.
the wave of the future:
Three papers published in August 2012 set off a surge of publicity in favor of the theory along with a skeptical backlash. For a summary, including citations, see Monya Baker, “Cancer Stem Cells Tracked,”
Nature
488, no. 7409 (August 2, 2012): 13–14.

11.
the annual meeting:
American Association for Cancer Research, 102nd Annual Meeting, “Innovation and Collaboration: The Path to Progress,” April 2–6, 2011, Orange County Convention Center, Orlando, Florida.

12.
more than 16,000 scientists:
“AACR Hosts Successful 102nd Annual Meeting in Orlando,” Previous Annual Meetings, AACR website. [
http://www.aacr.org/home/scientists/meetings-workshops/aacr-annual-meeting-2013/previous-annual-meetings/annual-meeting-2011.aspx
]

13.
an amazing video flythrough:
High-definition stills and videos in two and three dimensions are available on the Amgen website.[
http://angiogenesis.amgen.com
]

14.
Amgen had been working on an angiogenesis inhibitor:
Beth Y. Karlan et al., “Randomized, Double-Blind, Placebo-Controlled Phase II Study of AMG 386 Combined with Weekly Paclitaxel in Patients with Recurrent Ovarian Cancer,”
Journal of Clinical Oncology
30, no. 4 (February 1, 2012): 362–71. [
http://jco.ascopubs.org/content/30/4/362
]

15.
extended the lives:
The technical term used in the study was “overall survival.”

16.
“Judah is going to cure cancer”:
Gina Kolata, “A Cautious Awe Greets Drugs That Eradicate Tumors in Mice,
New York Times,
May 3, 1998.

17.
“the most exciting cancer research of my lifetime”:
James Watson, “High Hopes on Cancer,”
New York Times,
letter to the editor, May 7, 1998.

18.
“remarkable and wonderful”:
Kolata, “A Cautious Awe Greets Drugs.”

19.
metastasizing more vigorously:
Erika Check Hayden, “Cutting Off Cancer’s Supply Lines,”
Nature News
458, no. 7239 (April 8, 2009): 686–87. [
http://www.nature.com/news/2009/090408/full/458686b.html
]

20.
add a few months to a patient’s life:
Avastin product page, Genentech website. [
http://www.gene.com/gene/products/information/oncology/avastin
]

21.
the Food and Drug Administration … revoked approval:
Andrew Pollack, “F.D.A. Revokes Approval of Avastin for Use as Breast Cancer Drug,”
New York Times,
November 18, 2011. [
http://www.nytimes.com/2011/11/19/business/fda-revokes-approval-of-avastin-as-breast-cancer-drug.html
]

22.
standard chemotherapy was accompanied by Herceptin:
Edward H. Romond et al., “Trastuzumab Plus Adjuvant Chemotherapy for Operable HER2-positive Breast Cancer,”
New England Journal of Medicine
353, no. 16 (October 20, 2005): 1673–84. [
http://www.ncbi.nlm.nih.gov/pubmed/16236738
] Also see Luca Gianni et al., “Treatment with Trastuzumab for 1 Year After Adjuvant Chemotherapy in Patients with HER2-positive Early Breast Cancer: A 4-year Follow-up of a Randomised Controlled Trial,”
Lancet Oncology
12, no. 3 (March 2011): 236–244. [
http://www.lancet.com/journals/lanonc/article/PIIS1470-2045(11)70033-X/abstract
]

23.
Genentech could reduce the time to market:
An early end to a clinical trial is not necessarily considered a good thing. See F. Trotta et al., “Stopping a Trial Early in Oncology: For Patients or for Industry?”
Annals of Oncology
19, no. 7 (July 1, 2008): 1347–53 [
http://annonc.oxfordjournals.org/content/19/7/1347.abstract
]; Margaret McCartney, “Leaping to Conclusions,”
BMJ: British Medical Journal
336, no. 7655 (May 31, 2008): 1213–14 [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2405859
]; and Victor M. Montori et al., “Randomized Trials Stopped Early for Benefit: A Systematic Review,”
JAMA: The Journal of the American Medical Association
294, no. 17 (November 2, 2005): 2203–9. [
http://www.ncbi.nlm.nih.gov/pubmed/16264162
]

24.
a serious risk of congestive heart failure:
A study of twelve thousand women who took Herceptin found that mortality from breast cancer was reduced by one-third but that there was a fivefold increase in the risk of cardiac toxicity. See Lorenzo Moja et al., “Trastuzumab Containing Regimens for Early Breast Cancer,”
Cochrane Database of Systematic Reviews
2012, issue 4, article no. CD006243, published online April 18, 2012. [
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006243.pub2/abstract
]

25.
the “crowning achievement”:
Scott A. Stuart, Yosuke Minami, and Jean Y. J. Wang, “The CML Stem Cell: Evolution of the Progenitor,”
Cell Cycle
8, no. 9 (May 1, 2009): 1338–43. [
http://www.ncbi.nlm.nih.gov/pubmed/19342894
] For the story of Gleevec, see Terence Monmaney, “A Triumph in the War Against Cancer,”
Smithsonian,
May 2011. [
http://www.smithsonianmag.com/science-nature/A-Victory-in-the-War-Against-Cancer.html
]

26.
by strengthening the body’s immunological defenses:
For an overview see Ira Mellman, George Coukos, and Glenn Dranoff, “Cancer Immunotherapy Comes of Age,”
Nature
480, no. 7378 (December 21, 2011): 480–89; [
http://www.nature.com/nature/journal/v480/n7378/abs/nature10673.html
] Drew M. Pardoll, “The Blockade of Immune Checkpoints in Cancer Immunotherapy,”
Nature Reviews Cancer
12, no. 4 (April 2012): 252–64; [
http://www.ncbi.nlm.nih.gov/pubmed/22437870
] and David L. Porter et
al., “Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia,”
New England Journal of Medicine
365, no. 8 (August 10, 2011): 725–33.

27.
the patient’s own immune cells are removed:
In another approach, killed cancer cells are used to vaccinate patients against their own tumors in much the way that inactivated viruses are used to make influenza vaccines.

28.
as precipitously as they have for heart disease?:
Arialdi M. Miniño et al., “Deaths: Final Data for 2008,”
National Vital Statistics Reports
59, no. 10 (December 7, 2011). See figure 6, page 9. [
http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_10.pdf
]

29.
losing the War on Cancer?:
For a measured argument see Sharon Begley, “We Fought Cancer … And Cancer Won,”
Newsweek,
September 5, 2008. [
http://www.thedailybeast.com/newsweek/2008/09/05/we-fought-cancer-and-cancer-won.html
]

30.
founder and chairman of the advisory board:
Telome Health Inc. website. [
http://www.telomehealth.com
]

31.
said that she had lost her slide:
The speaker was Lynda Chin and the company is Aveo Oncology. Her husband is Ronald DePinho, who went on to become president of MD Anderson Cancer Center. In 2012 the couple was involved in a dispute over an $18 million grant. The details are reported in Meredith Wadman, “Texas Cancer Institute to Re-review Controversial Grant,”
Nature News,
May 31, 2012. [
http://blogs.nature.com/news/2012/05/texas-cancer-institute-to-re-review-controversial-grant.html
] Also see Meredith Wadman, “Texas Cancer-centre Head Apologizes for Promoting Stock on Television,”
Nature News,
June 1, 2012. [
http://blogs.nature.com/news/2012/06/texas-cancer-centre-head-apologizes-for-promoting-stock-on-television.html
]

32.
“I really want this stuff to work”:
Ervin J. Epstein, plenary talk, American Association for Cancer Research 102nd Annual Meeting, April 3, 2011. He also noted he had been a consultant for Genentech and Novartis and owned some stock in a company called Curis.

33.
pioneering work on viruses and oncogenes:
D. Stehelin, H. E. Varmus, J. M. Bishop, and P. K. Vogt, “DNA Related to the Transforming Gene(s) of Avian Sarcoma Viruses Is Present in Normal Avian DNA,”
Nature
260, no. 5547 (March 11, 1976): 170–73. [
http://dx.doi.org/10.1038/260170a0
]