44088
Turning cancer targets into treatments
- Best therapy for cancer is prevention
- Quit smoking
- Healthy diet
- Excercise
- Screening
- Applied to asymptomatic individuals
who fall within a risk group
- Sex, age, family history
- NHS currently screens for...
- Cervical cancer (24-50yrs)
- Colorectal carcinoma
- Breast cancer (45-69yrs)
- Cervical cancer (24-50yrs)
- Sex, age, family history
- Typical patient management
- Clinical findings
- Biopsy and imaging
- Diagnosis
- Staging/grading
- Therapeutic/surgical intervention
- Surgery
- Radiotherapy
- External beam
- Internal-brachytherapy
- External beam
- Chemotherapy
- Cytotoxic
- Biological (e.g. Herceptin)
- Hormonal
- Cytotoxic
- Surgery
- Therapeutic/surgical intervention
- Staging/grading
- Diagnosis
- Biopsy and imaging
- Clinical findings
- Applied to asymptomatic individuals
who fall within a risk group
- Quit smoking
- Tumour growth kinetics
- 10^5 cells (microtumour) - upper
limit for immunotherapy alone
- 10^5 - 10^12 cells - bulk tumour reduction necessary
(surgery, radiotherapy, multicourse intensive chemo)
- Diagosis poosible (symptomatic) around 10^9 cells
- Death at 10^12 cells (1kg of tumour)
- Diagosis poosible (symptomatic) around 10^9 cells
- 10^5 - 10^12 cells - bulk tumour reduction necessary
(surgery, radiotherapy, multicourse intensive chemo)
- 10^5 cells (microtumour) - upper
limit for immunotherapy alone
- Breast cancer
- Prognostic factors
- Tumour size (graded in TNM)
- Number of +ve axillary nodes
- Lymphatic/vascular invasion
- Histologic tumour type and grade
- Oestrogen/progesterone receptor status
- HER2 overexpression?
- Tumour size (graded in TNM)
- Early treatment
- Local control
- Surgery
- Radiotherapy
- Surgery
- Systemic treatment
for micrometastases
- Tamixifen if ER+ve
(25% reduction in
risk of death)
- Tamixifen if ER+ve
(25% reduction in
risk of death)
- Rehabillitation and surveillance
- For localised tumours 90% live >5yrs and >85% live >10yrs
- Local control
- Metastatic breast cancer
- ~5% of cases the cancer has already spread on first diagnosis
- Not curable - but controlled with treatment for some years
- Median duration of first endocrine response (taoxifen and arimidex - oestrogen inhibitors) = 20 months
- Median duration of chemo response (cyclophosphamide, epirubicin, 5-FU) = 10 months
- Median overall survival = 2yrs
- Stage 4 tumours have a 5yr survival rate of 13% and about 10% of women will survive >10yrs
- Palliative treatment for metastatic disease
- Targeting metastases
- We lack any detailed knowledge on the
metastatic process (for any cancer)
- Limits ability to design therapies - to date
angiogenesis inhibitors have proven diasappointing
- Limits ability to design therapies - to date
angiogenesis inhibitors have proven diasappointing
- We lack any detailed knowledge on the
metastatic process (for any cancer)
- ~5% of cases the cancer has already spread on first diagnosis
- Prognostic factors
- Major classes of cytotoxics
- DNA binding drugs
- Alkylating agents, platinums
- Cause direct damage and block replication
- Alkylating agents, platinums
- Antimetabolites
- Purine and pyrimidine analogues, antifolates
- Interfere with nucleotide synthesis, incorporated into DNA and block its replication
- Purine and pyrimidine analogues, antifolates
- Topoisomerase inhibitors
- Anthracyclines, TOPOTECAN
- Block action of enzymes involved in DNA
winding/unwinding - cause DNA strand breaks
- Anthracyclines, TOPOTECAN
- Tubulin acting drugs
- Vinca alkyloids, taxanes
- Inhibit microtubule formation (vincas)
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- Promote microtubule formation (taxanes)
- Block chromatid separation
- Block chromatid separation
- Vinca alkyloids, taxanes
- DNA binding drugs
- Topotecan (topoisomerase I inhibitor)
- Topoisomerase I is an enzyme that relieves
the torsional (twisting) strain in the DNA that
occurs during replication and transcription
- To do this the topoisomerase creates a single strand break -
allowing the DNA ahead of the replication fork to rotate freely
- Topotecan binds to topoisomerase and the DNA forming a stabile
ternary (three different molecules joined together) complex
- This prevents re-ligation of the DNA strand -damage
- Mammalian cells cannot efficiently repair
double strand breaks -> apoptosis
- Mammalian cells cannot efficiently repair
double strand breaks -> apoptosis
- This prevents re-ligation of the DNA strand -damage
- Topotecan binds to topoisomerase and the DNA forming a stabile
ternary (three different molecules joined together) complex
- To do this the topoisomerase creates a single strand break -
allowing the DNA ahead of the replication fork to rotate freely
- Topoisomerase I is an enzyme that relieves
the torsional (twisting) strain in the DNA that
occurs during replication and transcription
- New approaches to treating cancer
- Why?
- Cancer kills over 150,000
in the UK each year
- Existing treatment is effective but toxic
- Effectively crude poisons
- Effectively crude poisons
- Current treatments dont target
changes taking place in cancer cells
- Killing cancer cells is easy
- only killing them is hard
- Cancer kills over 150,000
in the UK each year
- New
compounds/novel
molecular
mechanisms
- Typically target specific proteins altered in cancer
- Designed from our better
understanding of what goes
wrong in cancer cells
- Philadelphia chromosome
- = shortened chromosome 22
- Translocation to chromosome 9
- Results in a fused protein: Bcr (chr22) and Abl (chr9)
- Abl is a tyrosine kinase - activates
other proteins (by phosphorylation)
- e.g. PI3K
- e.g. PI3K
- Bcr-fusion causes a constituitive activation of Abl
- Drives cell proliferation and blocks apoptosis
- These leukaemias are resistant to most anti-cancer drugs
- Imatinib (glivec) - the holy grail of cancer
- Glivec blocks the ATP site preventing
phosphorylation of the substrate (e.g. PI3K)
- Lack of kinase signalling inhibits proliferation and survival
- Lack of kinase signalling inhibits proliferation and survival
- Potent inhibitor of Bcr-Abl fusion protein and c-Kit
- Growth inhibition in CML and GI stromal tumous (GIST)
- Growth inhibition in CML and GI stromal tumous (GIST)
- Approved for clinical use after phase I/II data
- 98% haematological response with 13% remission
- 98% haematological response with 13% remission
- Substantial single agent activity in other tumours
(GIST) which are dependent on kinase signalling
- Glivec blocks the ATP site preventing
phosphorylation of the substrate (e.g. PI3K)
- Imatinib (glivec) - the holy grail of cancer
- These leukaemias are resistant to most anti-cancer drugs
- Drives cell proliferation and blocks apoptosis
- Abl is a tyrosine kinase - activates
other proteins (by phosphorylation)
- Results in a fused protein: Bcr (chr22) and Abl (chr9)
- Translocation to chromosome 9
- Clasic finding in CML
- = shortened chromosome 22
- Current UK approved
targeted treatments
- Rituximab (anti CD20 on B cells)
- Non-hodgkins lymphoma
- Non-hodgkins lymphoma
- Imatinib (glivec)
- Trastuzumab (herceptin)
- Bortezomib
- Myeloma
- Myeloma
- Cetuximab (anti-EGFR)
- Colorectal cancer
- Colorectal cancer
- IFN and IL-2 for melanoma
- Rituximab (anti CD20 on B cells)
- Typically target specific proteins altered in cancer
- Why?
- New therapeutic strategies
- Monoclonal Ab's
- Current MAbs: trastuzumab (HER2 breast cancer), cetuximab and
bevacizumab (colorectal cancer), rituximab (Non-hodgkin's lymphoma)
- Target: receptor ectodomain
- Specificity: ++++
- Binding: Recptor internalised
- slow regeneration
- Dosing: IV, weekly
- Tissue distribution: less complete
- Toxicity: rash, allergy
- Current MAbs: trastuzumab (HER2 breast cancer), cetuximab and
bevacizumab (colorectal cancer), rituximab (Non-hodgkin's lymphoma)
- Small molecule inhibtors
- Target: TK domain
- Specificity: +++
- Binding: most are rapidly reversible
- Dosing: oral, daily
- Tissue distribution: more complete
- Toxicity: rash, diarrhoea, pulmonary
- Target: TK domain
- RNA interference
- Gene therapy
- Some new therapies don't always work -
e.g.gefitinib (non-small cell lung cancer)
- Gefitinib had a less median survival rate
than the placebo group during phase III trial
- Gefitinib had a less median survival rate
than the placebo group during phase III trial
- Wnt singnalling inhibitors (anti-frizzled MAb's,
NSAIDs, Wnt MAb's, small ihibitory molecules)
- To target cancer stem cells (rely on normal
stem cell signalling - Wnt, SHH, Notch)
- e.g. Wnt signalling seen in prostate
cancer cells with stem cell characteristics
- e.g. Wnt signalling seen in prostate
cancer cells with stem cell characteristics
- NSAIDs (such as aspirin) shown to be of benefit
against Wnt-beta catenin reliant cancers (e.g. colon
cancer) due to the inhibition of COX enzymes
- COX converts arachidonic acid into
prostaglandin E2 (PGE2) which
inhibits beta-catenin degradation -
allowing Wnt/beta-catenin signalling
- The only NSAID licensed for treatment of familial
adenomatous polyposis is celecoxib (inhibitor of COX2)
- The only NSAID licensed for treatment of familial
adenomatous polyposis is celecoxib (inhibitor of COX2)
- COX converts arachidonic acid into
prostaglandin E2 (PGE2) which
inhibits beta-catenin degradation -
allowing Wnt/beta-catenin signalling
- New therapy: beta-catenin/CBP (TF complex that
promotes proliferation) inhibitors eliminates
imatinib (glivec) resistance in leukaemia stem cells
- To target cancer stem cells (rely on normal
stem cell signalling - Wnt, SHH, Notch)
- HH signalling
- Cyclopamine (natural compound from corn lily)
- Antagonist of activated smoothened
- Inhibits GLI activation and therefore inhibits HH signalling
- Inhibits GLI activation and therefore inhibits HH signalling
- Potential control over basal cell
carcinoma, medulloblastoma,
rhabdomyosarcoma (skeletal
muscle tumour)
- Antagonist of activated smoothened
- Erivedge - approved in use for
advanced/metastatic basal cell carcinoma
- Cyclopamine (natural compound from corn lily)
- Monoclonal Ab's
- Tumour targets
- Ras (K-ras, H-ras and N-ras
- point mutations in: pancreas (90%, k), thyroid (60%, h, k , n),
colon (45%, h, k, n), lung [nsc] (35%, k), melanoma (15%, k)
- Ras farnesyltransferase inhibitors
- point mutations in: pancreas (90%, k), thyroid (60%, h, k , n),
colon (45%, h, k, n), lung [nsc] (35%, k), melanoma (15%, k)
- GF eceptors
- Ecto domain
- MAb's
- Trastuzumab (Herceptin)
- HER2+ve breast cancer
- HER2+ve breast cancer
- Cetuximab
- EGFR - colorectal cancer
- EGFR - colorectal cancer
- Bevacizumab (avastin)
- Anti-VEGFR
- Anti-VEGFR
- Trastuzumab (Herceptin)
- MAb's
- TK domain
- anti-HER1/2/4 TK inhibitors
- ZD1839, OSI-774)
- ZD1839, OSI-774)
- anti-HER1/2/4 TK inhibitors
- Ecto domain
- BRAF (B-raf, MAPKKK)
- Raf inhibitors (BAY43-9006, PLX4032))
- Clinical trials vemurafenib (PLX4032) for use in melanoma
- 81% response rate
- Only works in B-raf with a V600 mutation
(i.e. valine at position 600 mutation)
- The most aggressive form of
metastatic melanoma
- The most aggressive form of
metastatic melanoma
- Approved for clinical use in V600 melanoma
- 81% response rate
- Clinical trials vemurafenib (PLX4032) for use in melanoma
- Raf inhibitors (BAY43-9006, PLX4032))
- mTOR
- mTOR inhibitors
- mTOR inhibitors
- MEK1/2 (MAPKK)
- MEK inhibitors
- MEK inhibitors
- Ras (K-ras, H-ras and N-ras
- Morning bunny :) xx
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