Introduction

• Little progress in cancer tx in the past 50 years
  • Exception is immunotherapy, but even this doesn’t widely apply and can have harsh side effects bc such efficient killing
• Focus must be on prevention and early detection, eliminating the first cancer cell

Chapter 1

• Slash/cut/burn protocol of tx (surgery, chemo, radiation) is often extremely painful— how often is no tx or palliative care offered as an option?
• Limitations of cellular and mice models of cancer
  • “If you’re a mice and you have cancer, we can take good care of you.”
  • Major differences btw mice and humans = much faster life cycle, metabolism of mice vs humans; difference in environment of evolution
  • Immune systems evolved to combat different types of pathogens → different compositions
  • Therapies that work both in vitro and in clinical settings are usually general cytotoxic agents (not specific to a gene or physiological process)
  • Even PDXs not particularly effective
• Need for fundamental shift in approach to treating cancer- interdisciplinary, multi-faceted
  • Shift from studying animals → humans
  • Shift from chasing the last cancer cell → detecting the first
• Currently, too much dependence on leaders in the field, grant funding, mentors
  • Can’t get grant $ without an animal model
  • Doctors need to spend more time with patients, understand the language of their illness, not just reaching for the first drug possible
  • Hippocratic Oath — “there is art to medicine as well as science”

Chapter 2

• Critical states and self-organization of sand— grain that causes a sand pile to collapse is no different than the rest → metaphor applies to cancer initiation as well
  • Suggests need to examine overall health (the soil) in addition to the first cell (the seed)
  • Accumulation of DNA mutations, exposure to internal and external cancer-causing agents (including pathogens like viruses, mutations to proto-oncogenes or tumor suppressor genes)
• Peto’s Paradox → mechanisms in large-bodied animals to prevent cancer
  • Value of comparative animals studies
• Cancer is a multi-organ disease almost immediately after it begins, even when confined to single site
• “The mist of aging” leading to cancer in the elderly — accumulation of mutations, decrease in functioning of immune system (like all biological systems with age), increase in number of senescent cells, tissue loss with age → spatial reorganization of cells

Chapter 3

• Precision medicine? Due to such heterogenous response to drugs
  • Identity molecular features of “unicorn” exceptional responders
  • Requires saving biosamples of biopsies of tumors, microenvironment— not being done currently
  • However: few cases of one gene driving malignancy; such mutations often don’t have matched drugs; even if there is, response rate remains low; and response only may mean an added 6 months vs other therapies
• Clonal composition of cancer → no person has one cancer; why one therapy rarely works forever

Chapter 4

• Research funding system is screwed up

Chapter 6

• Responsibility of oncologists to give patients efficacy, to offer all (applicable) treatment options
  • Currently often lack of trust btw doctor and patient → patients and their families Google all sorts of things
• Hope can be as harmful a disease as cancer
• Shift focus from tx targeting single genes to big data, omics, detecting DNA/RNA/proteins from the first cancer cells
  • CTCs, microRNAs, etc.