Intro to Cancer Therapeutics Flashcards
Epochs of Cancer treatment
Surgery, Radiation, Cytotoxic chemotherapy, combination chemotherapy, growth factor antagonism, specific immune therapy
adjuvant
systemic therapy given after surgery as an aid to achieving cure
neo-adjuvant
pre-operative therapy
single most conceptual advance in cancer therapy
combination of local and systemic therapy
Systemic therapies are usefully classified as
chemotherapy (poisons that inhibit mitosis or induce apoptosis)
Signal transduction inhibitors
Immune therapy
Central dogma
DNA – RNA – protein
Most pharmacology impacts
proteins (then intermediary metabolism) - least DNA and RNA
Where does protein regulation come at protein level
Protein-Protein interactions Glycosylation Phosphorylation Proteolysis Degradation (Ubiquitin)
Where do you regulate DNA to regulate proteins
Promoter •Transcription factors •Constitutive Expression •Silencing by Methylation Chromatin
how do you regulate RNA to regulate protein
Alternate splicing
iRNA
shRNA
Pathologic alterations of DNA
Viral Insertion Translocation Mutation Gain-of-function Loss-of-function Silent
Phases of mitosis
prophase prometaphase metaphase anaphase telophase
possible outcomes of mitotic arrest
(unattached kinetochores) – >
chronic arrest
adaptation, mitotic death
survival, apoptosis
Cancers are diseases of rapid/slow growth
Diseases of slow accumulation from failure to response to apoptotic signals
2 pathways of apoptosis
Intrinsic
FAS-mediated
Intrinsic apoptotic pathway
tbid - Cyto C –> casp 9 + apaf-1 –> apoptosome –> cleaved casp 9 –> cleaved casp 3 –> casp 7, apoptosis
FAS mediated pathway
Fas-ligand + receptor –> cleaved casp 8 – casp 3– casp 7, PARP – apoptosis
most drugs work where
proteins
fundamental, highly regulated process important both for neoplasia and sensitivity to chemotherapy
apoptosis
what is cancer
dysregulated growth characterized by loss of orientation and contact inhibition failure to respect anatomic boundaries immune evasion promotion of angiogenesis
what does cancer arise from
Arises from unbalanced growth promoting signals (“oncogenes”) with growth inhibitors (“tumor suppressors”)
human cancers are complex “organs” with
malignant cells, stromal cells, vasculature & immune infiltrates. They typically have very high interstitial pressure, low oxygen tension and low pH
how are cancers currently classified
Currently cancers are classified by tissue type of origin:
• Epithelial (carcinoma) ca. 70% of all cancers, named by anatomic site
• Stromal (sarcoma)
• Hematologic (leukemia, lymphoma, plasma cell dyscrasia)
• Germ Cell Tumors
cancer classification smart way
Soon, cancers will be classified on the basis of biology: What is driving proliferation What is inhibiting apoptosis What is promoting invasion What is promoting immune evasion etc.
