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Flashcards in Targetted Cancer Therapies Deck (23)
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1
Q

Cancer arises from…

A

-Imbalance of genetic events
-Tumor suppressor gene pathways
VS
-Oncogene pathways

2
Q

Oncogenes

A
  • Become activated - gain of function mutations
  • Involved in cell signal transduction and cell death signaling (inhibition of apoptosis)
  • Originally found in viruses, picked up protooncogene from host cell
  • Provide druggable targets
3
Q

Tumor Suppressor Genes

A
  • Become inactivated - loss of function mutations
  • Often involved in stabilizing genome, cell cycle regulation, and cell environment regulation
  • Categorized as caretakers/gatekeepers/landscapers
  • Difficult to target for pharmacotherapy
4
Q

Kinases

A
  • Enzyme that catalyzes phosphate transfers on amino acids

- Altered activity often seen resulting in increased cellular proliferation/survival

5
Q

Oncogene Activation Methods

A
  • Chromosomal translocations: abnormal expression or creates chimeric protein with unique activity
  • Mutations: point mutation that changes the amino acid sequence of the coded protein
  • Amplification: multiple copies of a gene leading to overexpression
  • Dysregulation: overexpression due to mutations in the promoter region
  • Proviral insertion: viral insertion alters gene expression
  • Others: alterations in phosphorylation
6
Q

Chromosomal Translocation Examples

A
  • Associated with Burkitt’s Lymphoma
  • Most common variant: t(8;14)(q24;q32)
  • Involves Ig genes (chr. 14) and c-myc (chr. 8)
  • Many other examples involving many different chromosomes
7
Q

BCR-ABL Kinase Inhibitiors

A
  • Activation of ABL oncogene occurs from translocation between chromosomes 9 and 22
  • Associated with chronic myeloid leukemia
  • Use Imatinib, dasatinib, nilotinib, bosutinib, or ponatinib
8
Q

Mutation Examples - KIT

A

Could result in…

  • Mutation of an oncogene, occurs as an early cancer development event and is important for maintaining cancer phenotype (oncogene addiction)
  • Drug resistance: occur after drug therapy is initiated, may takes months to years to develop, require changing drug used to inhibit activity
9
Q

EGFR

A
  • Epidermal Growth Factor Receptor
  • Several drugs developed to inhibit these receptors
  • Used in a variety of cancers (non-small cell lung cancer, breast, pancreatic)
10
Q

BRAF and MEK Inhibitors

A
  • BRAF-I used to treat melanoma
  • EX: Vemurafenib, Dabrafenib (first’s name comes from V600E mutated BRAF inhibition)
  • MEK-I: Used to treat melanoma
  • EX: Cobimetinib and Trametinib
11
Q

P13K Inhibitors

A
  • Blocks the phosphorylation of 3’ hydroxyl group of inositol ring used to cell signal transduction
  • Used to treat certain blood cancers
  • EX: Copanlisib, Idelalisib
12
Q

mTOR Inhibitors

A
  • Mammalian target, sensor for cellular nutrient, oxygen, redox, and energy levels
  • mTORC2 phosphorylates Akt
  • Used to treat breast cancer
  • EX: Everolimus
13
Q

ALK Inhibitors

A
  • ALK inhibitors or mutant ALK inhibitors
  • Used to treat non-small cell lung cancer
  • ALK Inhibitors: Alectinib, Brigatinib
  • Mutant ALK Inhibitor: Crizotinib
14
Q

BTK Inhibitors

A
  • Bruton’s tyrosine kinase plays key role in B-cell development
  • BTK Inhibitor: Acalabrutinib
  • Mutant BTK Inhibitor: Ibrutinib
15
Q

CDK Inhibitor

A
  • Cyclin-dependent kinases function in phosphorylating proteins involved in cell cycle progression
  • Palbociclib in a CDK-4 & 6 inhibitor
  • Used to treat ER+, HER2 negative breast cancer
16
Q

Thalidomide Analogs

A
  • Induce tumor cell apoptosis directly and indirectly by inhibiting bone marrow stromal cell support
  • Also by anti-angiogenic, anti-osteoclastogenic effects, and immunomodulatory activity
  • EX: Thalidomide, lenalidomide, and pomalidomide
17
Q

PARP Inhibitors

A
  • PARP is a large group of proteins involved in DNA repair and apoptosis
  • Treats ovarian and breast cancer
  • EX: Olaparib
18
Q

Isocitrate Dehydrogenase 2 Inhibitors

A
  • Used to treat acute myeloid lymphoma

- EX: Enasidenib

19
Q

Bcl-2 Inhibitors

A
  • B-cell lymphoma 2 protein is anti-apoptotic protein overexpressed in some cancers
  • Used to treat chronic lymphocytic leukemia
  • EX: Venetoclax
20
Q

HDAC Inhibitors

A
  • Histone deacetylase inhibitors
  • Used to manage cutaneous T-cell lymphoma
  • EX: Vorinostat
21
Q

Proteasome Inhibitors

A
  • Proteasomes ubiquinated proteins are proteolytically degraded
  • Inhibitor EX: Bortezomib, Carfilzomib, and Ixazomib
22
Q

Primary Resistance to Therapies

A
  • Inherent
  • Resistance in absence of prior treatment with agent
  • Mutations in susceptibility genes
23
Q

Secondary Resistance to Therapies

A
  • Acquired
  • P-gp and other efflux pumps
  • Increased drug metabolizing pathways
  • Expression of alternative targets
  • Deletion of drug target
  • Mutations in target
  • Upregulation of target
  • Upregulation of survival genes