Microtubule-based Cancer Therapeutics BIOS-010 September 12, 2018

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1 Microtubule-based Cancer Therapeutics 1 BIOS-010 September 12, 2018 Jessica C. Leung PhD Candidate Cassimeris Lab

2 What are microtubules? Why target them in cancer therapy? How do microtubule-based cancer therapies work? What is Taxol? What are the clinical limitations or implications of microtubuletargeting drugs? 2

3 Microtubules are a component of the cytoskeleton 3

4 Microtubules exhibit dynamic instability 4

5 Microtubules are also critical to cell division G2 M S G1 Interphase 5

6 MT dynamics essential to sister chromatid segregation 6

7 Preventing cell division to target over-proliferation normal cancer anti-mitotic drugs G2 M S G1 Interphase 7

8 Rationale behind microtubule-targeting drugs microtubule stabilizers [paclitaxel (Taxol )] microtubule depolymerizers [vinblastine, colchicine] Metaphase G2 M S G1 8

9 Rationale behind microtubule-targeting drugs microtubule stabilizers [paclitaxel (Taxol )] microtubule depolymerizers [vinblastine, colchicine] 9

10 Classes of tubulin-targeting drugs microtubule stabilizers [paclitaxel (Taxol )] microtubule depolymerizers [vinblastine, colchicine] Promote MT growth Stabilize MTs Increase MT polymer mass Prevent MT growth Destabilize MTs Decrease MT polymer mass g r o w s h o r t e n 10

11 Anti-mitotic mechanism of microtubule-targeting drugs microtubule stabilizers [paclitaxel (Taxol )] microtubule depolymerizers [vinblastine, colchicine] mitotic block cell death G2 S M G1 apoptosis (programmed cell death) 11

12 Taxol is a successful cancer therapy Taxol discovery timeline: Pacific yew tree 12

13 Taxol is a successful cancer therapy Taxol discovery timeline: Treats several types of cancer: ovarian, breast, lung, Kaposi sarcoma, cervical, pancreatic Treated over 1 million patients within first 10 years since approval (BMS) Continued success: WW sales ~$105 million (2015); ~$90 million (2016) (Evaluate Group) 13

14 Taxol inhibits microtubule dynamic instability Control 30nM Taxol 14

15 Taxol causes defects in spindle assembly 15

16 Reorganization of the MT array at mitotic entry Interphase Metaphase Mitosis G2 M S G1 Interphase 16

17 Microtubules reorganize at the start of mitosis Interphase Metaphase Mitosis ~5 min 17

18 Dynamics facilitate reorganization of the MT array Interphase Metaphase Mitosis 18

19 Dynamics at NEBD favors MT shortening to clear array Interphase Interphase Entering Mitosis g r o w catastrophe rescue s h o r t e n g r o w catastrophe rescue s h o r t e n rescue promoting catastrophe promoting rescue promoting catastrophe promoting 19

20 Dynamics at NEBD favors MT shortening to clear array Interphase Interphase Taxol Entering Mitosis g r o w catastrophe rescue s h o r t e n g r o w catastrophe rescue s h o r t e n g r o w catastrophe rescue s h o r t e n rescue promoting catastrophe promoting rescue promoting catastrophe promoting rescue promoting catastrophe promoting 20

21 Taxol should prevent entry to mitosis Taxol g r o w catastrophe rescue s h o r t e n Interphase Metaphase Mitosis 21

22 Taxol should prevent entry to mitosis but does not Therein, lies the conundrum of how cells respond to Taxol 22

23 Theoretical vs. actual cell cycle block in Taxol Taxol g r o w catastrophe rescue s h o r t e n 23

24 Theoretical vs. actual cell cycle block in Taxol 24

25 Taxol s MT-stabilizing activity is antagonized at mitotic entry Metaphase G2 M S G1 25

26 Taxol-treated cells exhibit a unique pattern of interphase MT array clearing Control Taxol 26

27 Taxol-treated cells exhibit a unique pattern of interphase MT array clearing Untreated Taxol 27

28 Why are Taxol-stabilized arrays sensitive to depolymerization specifically at the G2/M transition? What are the players Metaphase that can beat Taxol? Why now? G2 M S G1 28

29 Department of Biological Sciences Colloquium Seminar Series Jessica Leung PhD Candidate, Nemes Fellow Department of Biological Sciences, Lehigh University Thursday, September 27, 2018 Iacocca Hall, B-023 4:10 PM 29

30 Clinical limitations of Taxol (& other MTAs) Toxicity and side effects Hematological (blood) toxicity Neurotoxicity, neuropathy 30

31 Clinical limitations of Taxol (& other MTAs) Drug resistance Specific tubulin isotypes Altered microtubule dynamics Mutations to cell death pathway Membrane pumps and drug efflux G2 S M G1 apoptosis (programmed cell death) 31

32 MT-associated proteins (MAPs) as potential drug targets Many MAPs have critical roles during cell division Objective: Induce mitotic arrest, without affecting MT dynamics Efficacy of Taxol, without toxicities 32

33 MT-associated proteins (MAPs) as potential drug targets Mitotic MAPs MAP inhibitors in clinical development Rath and Kozielski. Nature Reviews

34 Potential implication of anti-mitotic drugs Selection for slow-growers / non-dividers Cancer stem cells normal cancer + anti-mitotic drug 34

35 Summary Microtubules are part of the cytoskeleton & play an essential role in mitosis Microtubule-based cancer therapies target dynamic instability & act as anti-mitotic agents Taxol is a microtubule-stabilizing drug & successful cancer therapy Clinical limitations: Side effects/toxicity, drug resistance, selection for slow/non-dividing cells 35