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Turning cancer targets into treatments
Descripción
Cancer Biology Mapa Mental sobre Turning cancer targets into treatments, creado por maisie_oj el 11/04/2013.
Sin etiquetas
cancer biology
cancer biology
Mapa Mental por
maisie_oj
, actualizado hace más de 1 año
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maisie_oj
hace más de 11 años
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Resumen del Recurso
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)
Typical patient management
Clinical findings
Biopsy and imaging
Diagnosis
Staging/grading
Therapeutic/surgical intervention
Surgery
Radiotherapy
External beam
Internal-brachytherapy
Chemotherapy
Cytotoxic
Biological (e.g. Herceptin)
Hormonal
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)
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?
Early treatment
Local control
Surgery
Radiotherapy
Systemic treatment for micrometastases
Tamixifen if ER+ve (25% reduction in risk of death)
Rehabillitation and surveillance
For localised tumours 90% live >5yrs and >85% live >10yrs
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
Major classes of cytotoxics
DNA binding drugs
Alkylating agents, platinums
Cause direct damage and block replication
Antimetabolites
Purine and pyrimidine analogues, antifolates
Interfere with nucleotide synthesis, incorporated into DNA and block its replication
Topoisomerase inhibitors
Anthracyclines, TOPOTECAN
Block action of enzymes involved in DNA winding/unwinding - cause DNA strand breaks
Tubulin acting drugs
Vinca alkyloids, taxanes
Inhibit microtubule formation (vincas)
Enter text here
Promote microtubule formation (taxanes)
Block chromatid separation
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
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
Current treatments dont target changes taking place in cancer cells
Killing cancer cells is easy - only killing them is hard
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
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
Potent inhibitor of Bcr-Abl fusion protein and c-Kit
Growth inhibition in CML and GI stromal tumous (GIST)
Approved for clinical use after phase I/II data
98% haematological response with 13% remission
Substantial single agent activity in other tumours (GIST) which are dependent on kinase signalling
Clasic finding in CML
Current UK approved targeted treatments
Rituximab (anti CD20 on B cells)
Non-hodgkins lymphoma
Imatinib (glivec)
Trastuzumab (herceptin)
Bortezomib
Myeloma
Cetuximab (anti-EGFR)
Colorectal cancer
IFN and IL-2 for melanoma
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
Small molecule inhibtors
Target: TK domain
Specificity: +++
Binding: most are rapidly reversible
Dosing: oral, daily
Tissue distribution: more complete
Toxicity: rash, diarrhoea, pulmonary
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
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
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)
New therapy: beta-catenin/CBP (TF complex that promotes proliferation) inhibitors eliminates imatinib (glivec) resistance in leukaemia stem cells
HH signalling
Cyclopamine (natural compound from corn lily)
Antagonist of activated smoothened
Inhibits GLI activation and therefore inhibits HH signalling
Potential control over basal cell carcinoma, medulloblastoma, rhabdomyosarcoma (skeletal muscle tumour)
Erivedge - approved in use for advanced/metastatic basal cell carcinoma
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
GF eceptors
Ecto domain
MAb's
Trastuzumab (Herceptin)
HER2+ve breast cancer
Cetuximab
EGFR - colorectal cancer
Bevacizumab (avastin)
Anti-VEGFR
TK domain
anti-HER1/2/4 TK inhibitors
ZD1839, OSI-774)
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
Approved for clinical use in V600 melanoma
mTOR
mTOR inhibitors
MEK1/2 (MAPKK)
MEK inhibitors
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