Telomerase and cancer therapeutics

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Telomerase and cancer therapeutics

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Outlines

• What is telomere?
• Telomerase as a therapeutic target
• Telomere length and cancer prognosis
• Telomerase-based cancer therapy
• Direct telomerase inhibition
• Active telomerase immunotherapy
• Telomere targeting agents

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What is telomere?
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Human Telomeres

• Non-coding DNA sequences at the end of
  chromosomes
• (TTAGGG)n hexanucleotide repeats
• During each cell division, telomeric DNA
  (30-100bp) is lost.
• Critical length ? determines human life span

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hTERT
hTR
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Action of Telomerase
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Telomerase as a therapeutic target
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History telomere and telomerase

• 1985 Discovered by Greider and Blackburn
• 1990 first recognized as a anticancer target
• 1995-2000 development of a sensitive assay for
  detecting telomerase in cancer and in normal
  tissues
• Now develop strategies and discover preclinical
  candidates for killing telomerase positive tumor
  cells

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Advantages of targeting telomerase

• Telomerase-positive tumors 80-90
• Cancer stem cells are also telomerase-positive
• No other tumor-associated gene is as widely
  expressed in cancers
• Tumors are less likely to develop resistance to
  telomerase-based therapies.
• Low or transient expression of telomerase in
  normal tissues ?broad therapeutic window

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Somatic cell

• Three check points
• Replicative senescence 5kbp
• Crisis 1-3kbp
• Telomere uncapping any length

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Germ cell
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Telomere length
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Telomere length and cancer prognosis
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The shortest telomere issue
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Assessment of telomere length may be used as
prognostic markers in solid tumors
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Telomerase-based cancer therapy

• Direct telomerase inhibition
• Active telomerase immunotherapy
• Telomere targeting agents

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Telomerase-based approaches to killing tumor cells
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Telomerase inhibitor

• BIBR1532
• GRN163L

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Structure and mechanism of GRN163L
Complementary to the hTR
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GRN163L In Vivo inhibition of lung cancer
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TIW treatment for 3 wks
off treatment for 5 wks
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GRN163L Treatment and Radiation Sensitivity
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Lessons learnt

• Phase I/II study to date
• Safety, tolerability, maximum tolerated dose
• Once weekly IVF, 3-4 weeks cycles, with dose
  escalation
• Ongoing trials

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Active telomerase immunotherapy

• GRNVAC1
• GV1001
• p540-548

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Telomerase mRNA-Transfected Dendritic Cells
Metastatic Prostate Cancer
J. Immunol. 174, 37983807 (2005).
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• Investigate the safety, tolerability and clinical
  response to vaccination
• Combination of telomerase peptides
• GV1001 (hTERT 611626) and HR2822
  (hTERT540548)
• 26 patients, advanced NSCLC
• Treatment period 10 weeks (low and high dose)
• Booster vaccination as follow up
• Immune response skin reaction, in vitro T cell
  proliferation

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In Vitro T Cell Response against GV1001
Before vaccination
after vaccination
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Conclusion

• The treatment was well tolerated with minor side
  effects
• No bone marrow toxicities were observed in long
  time survivors with immune responses.
• Immune responses11/24 patients, 2 additional
  patients after booster
• One patient had complete tumor response whose
  GV1001-specific cytotoxic T cells could be cloned
  from peripheral blood

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Lessons Learnt

• All phase I/II trials are open-label,
  non-randomized trials
• The signs of response were based on changes from
  the pre-treatment status and comparisons with
  historical controls
• The studies should be interpreted with caution

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Ongoing Phase III Trials

• Advanced pancreatic cancer
• 520 patients
• GV1001Gemzar vs Gemzar
• Advanced pancreatic cancer
• 1110 patients with sub-populations
• Three arms
• GemzarXeloda
• CT with sequential GV1001G-CSF
• CT with concurrent GV1001G-CSF

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Telomere targeting agents

• BRACO19
• RHPS4

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RHPS4 inhibits clonogenic tumour cell growth in
vitro and in vivo
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Tumor growth inhibition
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Green hTERT Blue DNA
hTERT Nucleus ? cytoplasm
Putative telomere-initiated DNA-damage
signalling ? 1hr maximal signal
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Tumor volume
Single-agent RHPS4 had limited In vivo
efficacy Combination of RHPS4 and taxol cause
tumor regression
Atypical mitoses
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Summary
Approach advantages Disadvantages
Telomerase inhibitor Amenable to small molecule drug development Safety margin based on known telomere length and telomerase activity Long response time Need sustained inhibition Long treatment duration may cause toxicity
Active immunotherapy May have life-long effect with periodic boosting May be effective in MRD May extend to prophylactic setting Immune compromised in many patient Manufacturing challenge
Telomerase-disrupting agents Rapid induction of cell death Amenable to small-molecule drug discovery Toxicity to normal cells Effective delivery throughout body is challenging
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What are the best patient populations?

• For telomerase inhibitor
• Rapid recurrence by minimal residual disease
• Short telomeres
• Combination therapy with radiation, cytotoxic
  agent, targeted therapy
• For telomerase immunotherapy
• Telomerase expression
• Status of immune system

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Thanks for your attention!!