Unit 1: Oncology Foundational Knowledge

Failure to differentiate characteristic of cancer cells

cells fail to develop specialized function, therefore they can proliferate faster

Loss of normal apoptotic pathways characteristic of cancer cells

cells have higher mutation rates and lose ability to undergo apoptosis, leading to increased tumor growth

Loss of replicative senescence characteristic of cancer cells

tumor cells have increased retention of telomeres via telomerase repair, making cancer cells able to divide an unlimited number of times

Non-responsiveness to growth inhibitory signals characteristic

loss of p53 activity occurs due to DNA damage/mutation, leading to unregulated growth of cells

invasion of surrounding tissues characteristic of tumor cells

tumors are supported by basement membrane of connective tissue and tumor cells must pass through this membrane to escape into surrounding tissue

metastasis to distant sites characteristic of cancer cells

once cancer cells invade basement membrane, they can enter lymphatic or blood vessels to metastasize to distant organs

shift in cell metabolism characteristic of cancer cells

tumor cells exist in O2 poor environment, therefore they utilize anaerobic respiration which is inefficient and means cancer cells have much higher need for glucose

Genetic instability characteristic of cancer cells

changes to genes and chromosomes that result in changes in protein expression or activity

Oncogenes

encode proteins that stimulate tumor cell function (good as drug targets)

Tumor suppressor genes

encode for proteins that inhibit tumor cell proliferation (genetic instability can decrease activity of these)

deregulated cell proliferation characteristic of cancer cells

gain of function or loss of function mutation in cell proliferation/apoptosis pathways lead to increased cancer cell growth

How is deregulated cell proliferation related to cytotoxic chemotherapeutic agents?

these agents target requirements for tumor cell proliferation (DNA repair, creation of building blocks (nucleotides), DNA synthesis, mitotic processes)

increased angiogenesis characteristic of cancer cells

creation of new blood vessels to supply tumors to allow growth via VEGF (released by cancer cell) and VEGFR (on endothelial cells)

Evasion of the immune system characteristic of cancer cells

cancer cells can induce CTLA-4 and PD-1 signaling which inactivates T-cells from recognizing the cancer cells as foreign

True or False: Tumors are caused by multiple genetic lesions?

True

Which 4 characteristics of cancer cells are relevant for current pharmacotherapy?

genetic instability, deregulated cell proliferation, increased angiogenesis, evasion of the immune system

General MOA of cytotoxic chemotherapy agents

target deregulated cell proliferation, required events for proliferation, and are more selective for tumor cells due to their extremely rapid division

Examples of rapidly dividing normal cells that account for ADRs of cytotoxic agents

hair follicles, skin cells, epithelium of GI tract, hematopoietic cells, cells of uterine lining and sperm

MOA of DNA Alkylating Agents

bulky group addition to DNA nucleotides and DNA cross-linking, which halts DNA replication, leading to cell apoptosis

Examples of DNA alkylating agents

mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil

MOA of Platinum Compounds

bulky group addition to DNA nucleotides and DNA cross-linking, which halts DNA replication, leading to cell apoptosis

MOA of 5-FU and Capecitabine

antimetabolites that directly prevent dUMP methylation to dTMP by thymidylate synthase, which decreases dTTP concentration, which inhibits DNA synthesis

MOA of Methotrexate and Pemetrexed

binds and inhibits dihydrofolate reductase which inhibits dUMP to dTMP converstion by prevention addition of the methyl group needed

Why is Leucovorin used alongside Methotrexate/pemetrexed?

It closely resembles FH4 and restores the normal concentration of N^5,10-methylene FH4, which allows normal cells to recover and still produce dTTP via TS, reducing the toxic effects of methotrexate/pemetrexed

MOA of topoisomerase inhibitors

inhibits topoisomerase from reconnecting DNA strands during replication leading to apoptosis

Examples of topoisomerase inhibitors

doxorubicin, daunorubicin, epirubicin, idarubicin

Why is doxorubicin knowns as the “Red Devil”

It is red in color and causes major toxicity in normal rapidly dividing cells. It also causes cardiotoxicity, leading to CHF, due to the quinone group creating ROS and causing oxidative stress

MOA of microtubule inhibitors

Inhibits lengthening and shortening of microtubule during Mitosis that leads to sister chromatid separation and creation of new daughter cells

Examples of microtubule polymerization inhibitors

Vinca alkaloids- vinblastine, vincristine

Examples of microtubule depolymerization inhibitors

Taxanes- paclitaxel, docetaxel

ADRs of microtubule inhibitors

Rapidly dividing normal cell side effects, also associated with myalgias and neuropathies due to microtubule need in brain for synaptic NT transmission

Which Vinca alkaloid is less neurotoxic than the other?

vinblastine

Three general principles for targeted chemotherapeutics

Genetic instability contributes to unregulated cell division, affects signaling pathways, and combo therapy is ideal due to multiple genetic changes and GP #2

BRAF mutation in melanomas

causes increased signaling of BRAF protein and other proteins that is a gain of function mutation

MOA of BRAF inhibitor (dabrafenib)

resembles ATP and competes for the ATP binding site on BRAF which inhibits further signaling of BRAF

Why treat BRAF mutation with both BRAFi and MEKi (trametinib)?

RTKs can stimulate multiple pathways, so it is important to block all possible pathways that lead to deregulated proliferation

MOA of immune checkpoint inhibitors

Inhibit CTLA-4 binding to APCs and PDL-1/2/ PD1 from binding to each other to up-drive T-cell activity

Immune checkpoint inhibitors examples

ipilimumab (CTLA-4), pembrolizumab (PD-1), nivolumab (PD-1), and atezolizumab (PD-L 1/2)

Which combination of immunecheckpoint inhibitors is best and why?

CTLA-4 with PD-1 OR PD-L 1/2 because the CTLA-4 mAb is functionally distinct from the other two

EGFR TK inhibitors MOA

compete with ATP for ATP binding site to inhibit signaling that drives uncontrolled tumor cell proliferation

Which cancer typically possesses EFGR TK mutations?

NSCLCs

Which EGFRTK inhibitors bind reversibly and why could that be a problem?

gefitinib and erlotinib, only effective against L858R mutation, other mutations may reduce their affinity

Which EFGRTK inhibitors bind irreversibly and are used most commonly today for EGFR mutant NSCLCs?

osimertinib and afatinib

Due to this chance for resistance development to EGFR TKIs, what can help determine the next steps?

Genetic testing

Example of an “on target” mechanism of resistance

EGFR T790M mutation

Example of an “off target” mechanism of resistance

increased MET signaling

When is sotorasib used and why?

to treat KRAS G12C mutant CRCs because it is specific to mutant KRAS and the cysteine replacement making it an irreversible inhibitor in the ATP binding site

MOA of cetuximab

binds to domain III of EGFR preventing binding of the rest of the molecule to its open conformation to allow EGFR dimerization/activation

MOA of Anti-HER2 antibodies trastuzumab and pertuzumab

Trastuzumab binds to HER2 subdomain IV and prevents homodimer (HER2/HER2) signaling; pertuzumab binds to HER2 subdomain II and prevent heterodimer (HER2/EFGR and HER2/HER3) signaling

Major ADR of anti-HER2 antibodies

Cardiotoxicity leading to CHF, therefore should not be used with doxorubicin

HER02 mAbs are particularly useful in what type of cancer

HER2-positive breast cancer

Why is estrogen suppression important in breast cancer

Many breast tumors depend on estrogen for proliferation, therefore suppression may be needed to prevent further tumor growth

MOA of Tamoxifen

partial agonist of estrogen that inhibits gene transcription leading to cell proliferation in breast tissue specifically

MOA of fulvestrant

estrogen receptor degrader that leads to full loss of receptor function

Aromatase inhibitors MOA and examples

prevent estrogen biosynthesis and are used in ER+/PR+ cancers; anastrazole/letrozole

Best treatments for ER+/PR+ Breast cancer

SERMS or AIs with CDK4/6 inhibitors for PI3K inhbitor

best HER2+ BC treatment

Combo of HER2 mAbs with Cytotoxic agent

triple-negative BC with BRCA mutation best treatment

PARP inhibitor and cytotoxic agent

CDK4/6 inhibitor MOA (Ciclibs)

prevents Rb phosphorylation at end of RAS/RAF/MEK/ERK pathway which prevents cell cycle progression from G0/1 to S phase and cells do not proliferate

PI3K inhibitors MOA (alpelisib)

inhibits PI3K from signaling to suppress apoptosis therefore promoting apoptosis

Why use anti-inflammatories (prednisone and dexamethasone) in cancer treatment

apoptosis causes inflammatory response which can damage normal cells/other tumor cells resulting in tumor progression

Angiogenesis inhibitors MOA

bbind to VEGF (bevacizumab) and VEGFR (amucirumab) to hinder VEGFR from promoting endothelial cell proliferation and organization into blood vessels to supply tumors

Some tumor markers don’t lead to malignant phenotypes (True or False?) and PSA can be used for what?

True, levels can be monitored to track disease progession/regression noninvasively