Precision Medicine: Cancer Drugs

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Job Gordon
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2 Precision Medicine Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.

3 Precision Medicine: Cancer Drugs

4 Precision drugs: magic bullets against cancer?

5 A common pitfall of targeted therapies: Acquired Resistance

6 A common pitfall of targeted therapies: Acquired Resistance

7 Genetic and Non-genetic routes to acquired resistance

8 Targeted drugs + Precision control

9 Precision Control of Protein Folding to treat Cancer and Neurodegeneration David Pincus Whitehead Institute for Biomedical Research commons.wikimedia.org

10 By the year Cancer (all types) 17.5 million deaths/year $1.7 trillion/year American Cancer Society

11 By the year Alzheimer s million dementia cases $1.1 trillion/year World Health Organization

12 Cancer and Alzheimer s are on opposite ends of the disease spectrum Alzheimer s premature cell death cancer unchecked cell growth

13 Patients with Alzheimer s have a lower incidence of cancer and vice versa Alzheimer s cancer e.g., Musicco et al. 2013, Neurology

14 Patients with Alzheimer s have a lower incidence of cancer and vice versa Alzheimer s cancer e.g., Musicco et al. 2013, Neurology

15 Patients with Alzheimer s have a lower incidence of cancer and vice versa Alzhemier s cancer e.g., Musicco et al. 2013, Neurology

16 Patients with Alzheimer s have a lower incidence of cancer and vice versa Alzhemier s cancer Same is true for Parkinson s and ALS vs. cancer e.g., Musicco et al. 2013, Neurology

17 Patients with Alzheimer s have a lower incidence of cancer and vice versa Alzheimer s PROTEIN FOLDING cancer Same is true for Parkinson s and ALS vs. cancer e.g., Musicco et al. 2013, Neurology

18 Genes (DNA) encode instructions to make strings of amino acids called proteins DNA RNA Protein

19 Genes (DNA) encode instructions to make strings of amino acids called proteins Protein folding DNA RNA Protein Functional Protein Proteins must fold correctly to carry out their functions

20 Proteins do not always fold properly proper folding

21 Proteins do not always fold properly proper folding misfolding

22 Proteins do not always fold properly proper folding misfolding aggregation misfolded proteins form aggregates

23 Protein aggregates are a hallmark of diseases like Alzheimer s Alzheimer s Parkinson s Huntington s mad cow ALS modified from Soto 2003, Nat. Rev. Neuroscience

24 Chaperones help proteins fold to prevent aggregation chaperones

25 Just like chaperones at your high school dance... images modified from: daily-player.com Meredith Brandimore netra.sptimes.com/tb-two

proteins from engaging in improper interactions images

26 Just like chaperones at your high school dance... aggregates folded proteins Chaperones prevent proteins from engaging in improper interactions images modified from: daily-player.com Meredith Brandimore netra.sptimes.com/tb-two

27 Chaperones perform protein origami chaperones images modified from: plus.maths.org simpleorigami.org

28 Chaperone levels drop in the brain as we age young brain aged brain chaperone levels age e.g., Yang et al. 2013, Neuron

29 Diseases like Alzheimer s occur in brains with low levels of chaperones.

30 Diseases like Alzheimer s occur in brains with low levels of chaperones. If we can increase chaperones in the brain, we can prevent and reverse these diseases.

31 Cancer progresses when cells acquire mutations in specific genes normal cell mutation arises unchecked cell growth

32 Mutations in genes make mutations in proteins normal cells proper folding cancer cells mutation misfolding Mutations make proteins difficult to fold

33 cancer Cancer cells hijack chaperones to counter the effect of mutations chaperones Cancer cells rely on elevated chaperone levels image modified from: colouringbook.org

34 Cancer cells hijack chaperones to buffer their mutations.

35 Cancer cells hijack chaperones to buffer their mutations. If we can decrease chaperones in tumors, cancer cells will self-destruct.

36 Cancer and diseases like Alzheimer s are mutually exclusive due to opposing requirements for chaperones Alzheimer s cancer

37 Cancer and diseases like Alzheimer s are mutually exclusive due to opposing requirements for chaperones Alzheimer s Chaperone levels drop, aggregates accumulate protein folding cancer Chaperones are hijacked to fold mutated proteins

38 Targeting chaperones is a game of Whack-A-Mole Alzheimer s cancer image modified from: raywenderlich.com

39 We need a Goldilocks approach just right too hot too cold porridge thermometer Targeted fine-tuning of chaperone levels is the goal

40 Reducing chaperone levels in a targeted manner is a general approach to treat all cancer types (breast, colon, pancreatic, lung, stomach, ovarian... )

41 Increasing chaperone levels in the brain is a general approach to treat all neurodegenerative diseases (Alzheimer s, Parkinson s, Huntington s, ALS, FTD... )

42 Tuning the chaperone dial for diseasespecific therapy breast cancer lung cancer pancreatic cancer ALS Parkinson s Alzheimer s Royce volume knob: uiparade.com

43 Tuning the chaperone dial for diseasespecific therapy breast cancer lung cancer HSF1 ALS Parkinson s pancreatic cancer Alzheimer s Royce volume knob: uiparade.com

44 HSF1 is the precision chaperone dial Dai. et al., 2007 HSF1 is required for cancer progression: turn it down in cancer HSF1 stops working in ND diseases: turn it up in Alzheimer s, etc.

45 Precision medicine needs a two-pronged approach 1. Target specific mutations that drive diseases (like oncogenes) 2. Fine-tune general cellular support systems (like chaperones)

Gene Regulation Part 2

Michael Cummings Chapter 9 Gene Regulation Part 2 David Reisman University of South Carolina Other topics in Chp 9 Part 2 Protein folding diseases Most diseases are caused by mutations in the DNA that