PMED in Oncology Flashcards
cancer 101
mutated cell
(uncontrolled growth)
primary tumour
(invasion and dissemination via blood and lymphatics)
metastatic tumour
or
treatment - remission
recurrence
what are the molecular aspects of cancer
genetic alteration (mutation)
altered protein (mutant form, overexpression)
altered pathways (activated cell survaval, loss of apopototic signals
altered biology
(limitless replication, angiogenesis, tissue invasion)
cancer treatment options?
surgery radiotherapy chemo hormonal targeted therapy adjuvant therapy palliative care
define overall survival
length of time that patients are
alive, from either diagnosis or commencing treatmen
define progression free survival
length of time that
patients have disease but it does not get worse
define disease free survival
length of time after completing
treatment without any signs or symptoms of cancer
define response rate
percentage of patients whose cancer
shrinks or disappears after treatment
traditional diagnosis steps
1) site
2) invasion
3) histology
4) differentiation
traditional primary characteristic of cancer
uncontrolled cell division
traditional primary cancer treatment
chemotherapy - which inhibits DNA replication, disrupts microtubule function
what does tamoxifen do?
used for the treatment of both early and advanced estrogen receptor (ER)-positive (ER+) breast cancer
acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited
modern primary characteristics
specific mutations drive cell division
modern primary treatment
targeted therapy
what is gleevec/imatinib?
chemotherapy medication used to treat cancer. Specifically, it is used for chronic myelogenous leukemia (CML)
what is the philadelphia chromosome assoc with and what is it?
CML
Specific genetic abnormality in chromosome 22 of leukemia cancer cells
This chromosome is defective and unusually short because of reciprocal translocation of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is “always on”, causing the cell to divide uncontrollably
what is HER2?
member of human epidermal growth factor receptor
role of HER2 in cancer?
Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.It is strongly associated with increased disease recurrence and a poor prognosis
what is heceptin/trasruzumab?
humanised monoclonal antibody against HER2.
how doesherceptin/trastuzumab work?
Dimerised
HER2 receptors
signal to cells
to proliferate
Herceptin flags cells for immune- mediated death (antibody dependent cellular cytotoxicity, ADCC
Herceptin blocks downstream
HER2 signalling,
inhibiting proliferation
what was the response to herceptin?
Progression free survival increased from 4.6 to 7.4 months
•
Longer response to treatment, from 6.1 to 9.1 months
•
Increased survival, from 20.3 to 25.1 months
name another anti-her2 therapeutic agent and how is it different
pertuzumab
targets a different part of the HER2 receptor.
Can use both pertuzumab and herceptin so they work synergistically.
what is trastuzumab(herceptin)emtansine?
herceptin that is conjugated to emtansine.
Trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor. can also bind to EC domain, draw in immune system to kill
whereas emtansine can get takin into cells and broken down emantine is liberated and destroys them by binding to tubulin - disrupting microtubule assembly.
get 3 mechanisms of action in one.
how is HER2 detected?
using IHC (immunohistochemistry) and FISH (fluorescence in situ hybridisation)
what is lapatinib
tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways.
Can use all 3 together.
what is anaplastic lymphoma kinase (ALK)?
Cell surface receptor with intracellular TK domain • Wild type activation: ligand binding, dimerization, autophosphorylation • Associated with: cell - cycle progression, survival, proliferation, angiogenesis.
What is EML4-ALK
Its a fusion oncogene
get inversion in chr 2 which brings together half of EML4 and half of ALK = fusion gene, constantly active
What is EML4-ALK associated with?
found in non-small cell lung cancer
what is PF-02341066
A drug used to treat non-small cell lung cancer that has spread to other parts of the body.
It is a cMet (tyrosine protein kinase Met) selective tyrosine kinase inhibitor.
Also an inhibitor of the ALK tyrosine kinase
what does PF-02341066 do?
It is used in patients whose cancer has a mutated (changed) form of the anaplastic lymphoma kinase (ALK) gene or the ROS1 gene.
PF-02341066 blocks the proteins made by the mutated ALK genes. Blocking these proteins may stop the growth and spread of cancer cells.
PF-02341066 may also prevent the growth of new blood vessels that tumors need to grow. It is a type of tyrosine kinase inhibitor and a type of antiangiogenesis agent.
Also called crizotinib, MET tyrosine kinase inhibitor PF-02341066, and Xalkori
what was the ALK therapy used called and what was its response?
crizotinib, 50%
better to start with 1st or 2nd gen drug?
trials show, better to start with 2nd gen drug as they are more potent/effective
how does drug resistance occur?
1) you’ve got a mutated cell, forming a tumour. However the tumour is not homogenous, not same clonal expansion of that original cell. There are different cells within that tumour each with their own mutations.
2) when you treat tumour with targeted therapy, you are killing most of the cells in that tumour, but there are some which will be resistant in someway which can go and form a second tumour.
Alternativley you afre creating a selection pressure (drug) which kills of most cells, leaving a few behind which can survive.
what are the mechanisms of tumour resistance?
1) survival of the fittest
2) sometimes the tumour will develop a secondary mutation which give rise to resistance.
3) ALK amplification
4) activating alternative signalling/pathways
5) upregulation of frug efflux pump p-glycoprotein (MDR1)
how can secondary mutation give rise to resistance (ALK-TKI)?
the resistance can hinder the drug binding to the TK, alter kinase conformation, affects binding affinity for ATP of the TK
explain ALK amplification
amplification of fusion genes in subset of genes and when tumour reoccurs youi see cells all contain that ALK
explain upregulation of efflux pump
upregulation of a pump which can pump the drug out of the cancer cell
what is the classic gene involved in upreg of drug efflux pump and what does it code for?
Multi-drug resistance 1 gene (MDR1) codes for p-glycoprotein
what drug is used against efflux pump?
can give verapamil (alongside crizotinib) - which inhibits p-glycoprotein
what does EGFR stand for?
epidermal growth factor receptor
structure of EGFR?
extracellular domain, transmembrane domain, intracellular tyrosine kinase domain
EGFR role in cancer?
common mutations in the IC TK domain, which activate the TK domain which then activated downstream signalling pathways which then gives cancerous phenotype
drug against EGFR?
EGFR TKI such as gefitinib
what drug is used in melanoma and how does it work?
vemurafenib - targets the v600e mutation in BRAF.
second gen: trametinib
advantages of targeted therapies
Exceptional responses in some patients
Increased survival
Well tolerated compared to cytotoxic chemotherapy
problems w targeted therapies?
1)Most patients lack the molecular changes treatable with current molecular therapies e.g V600E BRAF ≈ 50% (melanoma) HER2 overexpression <30% (breast) HER2 overexpression <20% (gastric) EML4ALK translocation <6% (NSCLC)
2) Clinical trials: must recruit many patients to identify
sufficient with the molecular change e.g oGA
Trial of
Herceptin in gastric cancer:
recruited ~4000 patients
<600 treated
what is basket/bucket trial?
one drug, many tumour types eg ALK inhibitor
what is umbrella trial?
one tumour type, treat with lots of drugs ie. lung `cancer
what is NCI-MATCH?
National Cancer Institute - Molecular Analysis for Therapy Choice. Trying to find 6000 patients with solid tumours, lymphoma and myelome. DNA seq of 142 key genes.
Depending on which mutations are present of those genes, the patient will go into on of 24 arms of clinical trials.
more problems with targeted therapies?
1) Most patients lack targets
2) Clinical trial recruitment and design
3) Evolution of resistance
4)Relatively short survival gains - Ceritinib , no improvement wrt chemotherapy - Herceptin, 5 month gain (25 month total) - Pertuzumab , 16 month gain (56 month total)
5)Expensive - Pertuzumab , £16,765 - Nivolumab (melanoma), £5,700/month
what is early stage breast cancer?
breast cancer which has not spread
how you treat early stage breast cancer?
surgery (lumpectomy, mastectomy)
adjuvant therapy: radiotherapy, chemotherapy, hormone therapy (ER+ve tamoxifen)
need to predict recurrence in patients with LN -ve, ER+ve breast cancer
how to predict patients whos cancer will recur
measuring gene expresion using microarrays
give name of microarray that predicts recurrence in breast cancer
oncotype Dx
what did NICE(2013) conclude the best predictor?
oncotype Dx
how does oncotype Dx work?
uses 21 genes
uses qRT-PCR
what was the impact of the oncotype Dx
Decreased chemotherapy use
Increased confidence in decision making
Cost effective in the UK
what to do with intermediate patients?
trial assigning individualized options for treatment (TAILORx)
findings (sparano et al 2015) foung 16% of patients were lo risk and entered arm A, recieving hormone therapy alone, 98% still alive after 5 years.
concluded patients with a low risk repxression profile can be spared chemo and their risk of recurrence within 5 years is less than 2%.
traditional method of monitoring disease?
imaging using CT and PET
molecular markers: PSA, CA15-3
what is metastasis?
when you have a primary tumour, some cells break away and invade the blood circ and lymphatic system. Circulate round going elsewhere to distant sites and form a tumour in new location.
circulating tumour cells?
found in absence of signs of metastasis
found months/years after resection
cell count correlates with prognosis (miller et al 2010)
cell free DNA (cfDNA)
some dna is found free floating in blood (short fragments). Unknown reason.
sequence primary tumour and normal cells, identify tumour specific genomic variants, blood sample, isolate DNA from plasma, PCR amplification, sequencing and quantitation of tumour-specific mutations indicated tumour burden.
advantages of CTC and cFDNA?
More sensitive than imaging techniques
Less invasive than biopsy
Longitudinal sampling to monitor disease
progression and response to treatmen
