Introductory Remarks

1
Introductory Remarks

• Prof. Stan B. Kaye, MD
• The Royal Marsden HospitalSutton, UK

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Selecting the targets

• Microtubules play a role in regulating multiple
  intercellular functions including mitosis,
  maintenance of cell shape, and transport.
• Microtubule-targeted agents bind to tubulin and
  prevent the depolymerization of microtubules.
• mTOR functions as a biologic switch, responding
  to signals of cellular processes that regulate
  cell growth and motility, initiate and maintain
  cell division, and regulate the internal
  machinery of cell death.
• mTOR targeted agents may therefore possess broad
  anti-tumouractivity and properties, including
  angiogenesis inhibition.

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Microtubule composition and dynamics

• Microtubules composed of1,2
• Tubulin dimers (primarily a and ß)
• Microtubule-associated proteins
• Dynamic microtubule assembly/disassembly vital
  for1,2
• Mitosis
• Maintenance of cell shape
• Intracellular transport

1Dumontet C and SikicBI. J Clin Oncol.
1999171061-1070.2Erickson HP et al. J Cell
Biol. 19961355-8.
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Growth factors and the mTOR pathway

• mTOR
• Intracellular protein
• Central controller of cell growth
  andproliferation
• mTOR signaling is often deregulated in cancer
• Downstream inhibition of mTOR has potential for
• Antiproliferative effects on tumor cells
• Angiogenesis inhibition
• Enhancement of the effects of chemotherapy

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Promising new agents

• Microtubule-targeted agents PATUPILONE
• has antitumor activity against a broad range of
  tumors
• has an acceptable safety profile
• more potent than taxanes
• mTOR targeted agents RAD001 (Everolimus)
• blocks mTOR function
• promising results in NET and metastatic RCC

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Current microtubule-targeted agents Taxanes

• Paclitaxel and Docetaxel
• Efficacy
• Widely used in breast, lung, ovarian, prostate,
  head and neck, bladder, and esophageal cancer1
• Taxane resistance is common2
• P-glycoprotein (P-gp) efflux pump
• Tubulin mutation/overexpression
• Toxicity1,2
• Myelosuppression
• Neurotoxicity
• Myalgia
• Major hypersensitivity

1Dumontet C and Sikic BI. J Clin Oncol.
1999171061-1070. 2Rowinsky EK. Annu Rev Med.
199748353-374.
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Microtubule-targeted agents Need for innovation

• Given the efficacy and toxicity limitations of
  the taxanes, there is a clear need for the
  identification of novel cytotoxic anticancer
  agents with an improved overall therapeutic
  profile including
• broad spectrum of anti tumor activity
• efficacy against resistant tumors
• safety and tolerability

1Dumontet C and Sikic BI. J Clin Oncol.
1999171061-1070. 2Sangrajrang S et al. Int J
Cancer. 199877626-631.