Lecture 7 - target therapy 1 Flashcards
what are the definitions of targeted therapy?
Attempt to take advantage of genetic change in the malignant cells
Drugs target processes, pathways, and pathologies which are uniquely distributed in cancer cells eg
- receptors
- genes
- angiogenesis or metastases
- antigens expressed
- microenvironment - hypoxia
describe chemotherapy vs targeted therapy
chemotherapy is when;
drugs that effect doubling cells
not very specific
many are IV, some are oral
drugs gave acytotoic effect - killing cells
targeted therapy:
more specific drugs targeted in cells
many are oral agents
have a mix of cytostatic - stopping cells and cytotoxic effect
what are examples of targeted in cancer cells?
signal transduction/ cell cycle inhibitors - TKIs, CDK inhibitors
angiogenesis inhibitors - anti-VEGF, endothelin inhibitors, thalidomide
receptor targeted therapy - anti-HER2 and anti-EFR
gene targeted therapy - targeting p53, pRB, antisense, and specific gene targeted therapies
immunological activation/ tolerance
what are the best targets?
best targets are one in a cancer cell but not normal cell. can also use targets that are more targets or mutated/different in cancer cells than normal cells
what is personalised medicine?
personalised medicine is the use of moelcucualr analysis for optimum treatment for the management of patient disease
positives are
Detect disease at earlier stage – easier to treat
Enable selection of optimal therapy and reduce trial and error prescribing
Reduces adverse reactions
Reduce time, cost and failure rates of clinical trials
Reduce the overall cost of healthcare
negatives are
cost of tests and time to do them
delay to start of treatment waiting for tests
smaller market for pharma- are they bought in?
drugs themselves are expensive and not accessible to everyone
Need good biomarkers to be able to stratify patients
Need good biomarkers in the form of liquid biopsy to monitor response or
Development of resistance
Resistance often develops
what are the diagnostics for personalised medicine and their values?
predispositions screen - identify patients for chemo-prevention
screen for presence of cancer - increase in patient; earlier disease
pharmacodynamic biomarker - establish pharmacological dose
surrogate marker of clinical efficacy - early indication of proof of efficacy
what are examples of personalised medicine in breast cancer?
HER1-/neu receptor - select Herceptin (trastuzumab) for breast cancer
BRCA1/2 - breast and ovarian cancer inherited risk, prophylactic tamoxifen and surgery
21 genes - avoid use of chemotherapy is breast cancer patients with low risk of recurrence
explain how Herceptin may work
HER2 receptors send signals telling cells to divide and grow. Too many HER2 receptors send more signals, causing cells to grow too quickly. Herceptin may stop the HER2 receptors from signalling the cell to grow. In addition to stopping growth signals Herceptin can also
Induce an immune response against the tumours with Herceptin
attatched
what is chronic myeloid leukemia?
CML is the result of a reciprocal translocation between chromosome 9 and 22.
The result is a fusion gene created by juxtapositions the ABL1gene and Some 9 to part of the BCR forming oncogenic BCR-ABL gene fusion.
BCR-Abl expresses tyrosine kinase so is also translated into very active tyrosine kinase
ABL activates many. cell cycle-controlling proteins and enzymes, the result of
the BCR-Abl fusion is to speed up cell division and inhibits DNA repair
what is the cause and management of chronic myeloid leukaemia?
the Ph chrmsoosme generates the Bar-Abl tyrosine kinase which is the molecular cause of CML - leads to malignant transformation.
eliminating Ph chromosome is a primary goal of therapy
what is imatinib and what is its mode of action?
imatinob is a drug used to target the BCR-Abl tyrosine kinase. only present is MCL cells
moa: inhibits Bcr-Abl tyrosin kinase, the constitutive abnormal gene product of the Philadelphia chromosome in CML. slots into the ATP binding site so ATP cannot be switched on. no substrate present so target proteins cannot be phosphorylated
how has gleevec advanced the treatment of Ph+ CML?
therapy specifically designed to target the meolcalr cause of MCL (Bar-ABL)
high rates of cytogenetic and hematologic responses in all phases of disease
significant delay in time to disease progression for patients in chronic phase
model to moderate side effect profile
convenient, con daily oral dosing
evolving first-line therapy for cml
how to detect the Philadelphia chromosome?
Fluorescence in situ hybridization (FISH): This is a molecular cytogenetic technique that uses fluorescent probes to detect specific DNA sequences. It can identify the presence of the BCR-ABL fusion gene, which is formed as a result of the Philadelphia chromosome
what are examples of modified imatinib?
second degeneration tyrosine kinase inhibitors:
Nilotinib- modification of Imatinib
structure to allow tighter binding
Dasatinib- fewer structural constraints
to binding
- targets more kinases
what are experimental therapeutic approaches for targeting metastasis?
Fragmin, which is a type of matrix metalloproteinase (MMP) inhibitor, is a drug that can help inhibit the migration of tumor cells.
complex cytotoxic drug to cell surface molecules such as adhesion molecule, LDL receptor, hormone receptor and protease that is over expressed inmestastic cells
