CANCER

oncogenes

________________ drive cancer progression

tumor suppressors

______________ inhibits cancer progression

DNA proofreading and repair

What is critical in the prevention of cancer?

surgery, radiation, chemo, palliative care

Ways to treat cancer - general

Neoadjuvant

BEFORE SURGERY (see if it shrinks)

Adjuvant

after surgery for the residuals

Maximum tolerated dose (low TI)

Chemo dosing is based on

prevents resistance

Why is combination therapy the norm for chemo?

supervised IV dosing (low TI), hormonal-based or kinase inhibitor may be given orally

Route of administrations for chemo

S phase, M phase

Most chemo drugs target what - efficacy is based on the concept that cancer is a disease of rapidly dividing cells

antimetabolites, DNA damaging agents

Agents that target the S phase (synthesis of DNA)

microtubule targeting drugs

Drugs that inhibits the M phase (mitosis)

Crosslink and damage; inhibit synthesis or transcription, repair inhibitors

Ways that chemo disrupts the DNA

Cyclophosphamide (alkylating agent), cisplatin (platinum drug)

Examples of Chemo agents that crosslink and damage DNA

Doxorubicin (intercalating agent (no unzipping these genes)), 5-FU/MTX (antimetabolites), Topotecan (topoisomerase inhibitorsin)

Examples of Chemo agents inhibit DNA synthesis and transcription

PARP inhibitors

Examples of Chemo agents that inhibit DNA repair

Doxorubicin

Which chemo agent is produced from soil-based streptocyces peucetius and is commonly used for leukemias, lymphomas, bladder, breast, stomach, lung, ovarian, thyroid, sarcoma, and myeloma

Cardiotoxicity (rapid development of heart failure)

What is the dose-limiting effect of doxorubicin - dose dependent and cumulative

Doxil (liposomal formula, deposits in the skin)

If doxorubicin is working great on your patient, but they start to get cardiac side effects, what can we switch them to?

-platins

Examples of platinum agents

neurotoxicity (cisplatin), nephrotoxicity (cisplatin), myelosuppression (carboplastin), hearing loss

ADRs for the -platins

testicular, ovarian (carboplatin), cervical, breast, bladder, head, neck, lung, brain, colorectal (oxaliplatin)

Indications for platinum agents (use in combination…)

thymidine synthase inhibitor (anti-metabolite)

MOA for 5-FU (5-fluorouracil)

breast, colon, rectum, stomach, pancreas, BCC skin cancers

Indications for 5-FU

inflammation of the skin and mouth, CNS damage, diarrhea

ADRs for 5-FU

If we knock out all the pathways for repair → cancer cell dead (watch in peds can give rise to secondary cancers)

Okay so if DNA damage causes cancers, why are we causing more to cure it??

Normal cells have BRCA to fall back on - the others don’t

Why are PARP inhibitors “selective” in a sense for BRCA deficient cells?

Destabilizers (destroy the structure), stabilizers (clump’em together)

Categories of microtubule targeted drugs

Vinca alkaloids (vinblastine, vincristine), eribulin

Microtubule destabilizers can be used in lymphoma, leukemia, sarcoma, neuroblastoma, testicular and lung cancers - what are some examples

Taxanes (paciltaxel, docetaxel), Ixabepilone

Microtubule stabilizers can be used in ovarian, breast, lung, cervical, pancreatic, stomach, prostate, head and neck cancers - what are some examples

rapidly dividing tumors, hematological malignancies, slow-growing tumors, or nondividing cells (slow the signal transduction because there’s no traintracks)

Microtubule targeted drugs are effective in

Bone marrow suppression, GI disturbance (mucositis), alopecia, Neurotoxicity (peripheral neuropathy is dose limiting)

ADRs of antimiotic chemo

CD30 antigen

What is a defining marker of lymphomas

MMAE (monomethyl auristatin E)

What is effective at targeting CD30 but must be attached to an antibody (suicide bomber style)

peripheral neuropathy, neutropenia

Dose limiting effects of MMAE

slow growth (mutate in the midst of chemo), efflux pump (chemo can’t act), evade the immune system (no CD8 or NK response)

Mechanisms of resistance in cancer cells

mutation at the specific binding site, a different driver (upregulation of complementary pathways), efflux pumps

Innate resistance of cancer cells can be due to

breast, prostate, ovarian

Cancers driven by hormones

binding of hormone to intracellular receptor, nuclear translocation of receptor, regulation of gene expression drives the growth

Hormone driven cancers require 3 steps what are they

LH releasing hormone (LHRH) agonist, LH antagonist, androgen receptor antagonists,

Which classes of medications can be used for androgen deprivation therapy (ADT) for the treatment of androgen dependent prostate cancer

leuprolide, goserlin (note: testosterone flairs initially then crashes in about a month)

Examples of LHRH agonists

degarelix (no flair)

Examples of LH antagonists

hot flashes, decreased bone density, loss of muscle mass, weight gain, insulin resistance, ED, low libido, cognitive impairments

Side effects of Androgen deprivation therapy - think menopause

Bicalutamide (partial agonist), Enzalutamide (multiple spots of inhibition)

Examples of androgen receptor antagonists (effective even in castration resistant tumors)

taxane-based chemo (microtubule disruption)

ADT has an initial response rate of 80-90% but nearly all men progress to castration resistant prostate cancer - what do we do now?

decreased estrogen levels, inhibit estrogen receptor mediated transcription

Strategies for inhibiting estrogen signaling

Aromatase inhibitors, Estrogen receptor antagonists

Gameplan for post-menopausal women or those with NO ovaries

GnRH/LHRH agonists, SERMs

Gameplan for pre-menopausal women with ER-positive breast cancer

tamoxifen (antagonist in breast, agonist in uterus and bone)

Examples of SERM

anastrozole, letrozole, exemestane

Examples of aromatase inhibitors

fulvestrant

Examples of estrogen receptor antagonists

Trastuzumab (herceptin - targets and neutralizes the receptor, can add a conjugate to the antibody)

What is the gameplan for HER-2 positive cancers? (used in combination)

immunotherapy + chemo

What is the gameplan for triple negative breast cancer?

single chromosomal translocation generating BCR-ABL on a philly chromosome

CML can be caused by a

Imatinib (gleevec - kinase inhibitor)

What drug can selectively block BCR-ABL activitty

when the main driver of the tumor can be inhibited

When are kinase inhibitors helpful

VEGF inhibition, VEGF kinase inhibitor

What drug classes target the angiogenesis of cancers

bevacizumb (avastin)

Examples of VEGF inhibitors (useful for cervical, colorectal, glioblastoma, ovarian, renal)

Sorafenib (HCC, renal, thyroid), Sunitinib (GI, pancreatic, renal)

Examples and uses of VEGF kinase inhibitors

hemorrhage, clots, HTN, healing defects, GI perf, fatigue, diarrhea, heart failure

Side effects of anything that target angiogenesis

checkpoint inhibitors (note: you need the TCR/HLA action for these to work)

Immunotherapy classes of anticancer drugs

PD-1 inhibitors (CD8), PD-L1 inhibitor (cancer cell), CTLA-4 inhibitor

Classes of checkpoint inhibitors

Pembrolizumab (keytruda - melanoma, lung, head, neck), Nivolumab (melanoma, lung, renal, lymphoma)

Examples of PD-1 inhibitors

Atezolizumab, durvalumab

Examples of PD-L1 inhibitors (Used for urothelial, lung)

ipilimumab (melanoma)

Examples of CTLA-4 inhibitors

patients with high mutational burden (long-term survival advantages in 30%)

Checkpoint inhibitors work by letting the immune system go crazy - when is the useful?

Autoimmune effects (could be a delayed onset), EXPENSIVE AF

ADRs for checkpoint inhibitors

Phase 1 (safety) → Phase 2 (effective) → Phase 3 (compare to the STANDARD - not ethical to use placebo)

Describe the clinical trial process for chemo agents

early diagnosis, new therapeutic options, better management of toxicities

What causes an increased survival in cancer?

secondary cancers, long term toxicities, financial debt

Challenges of surviving cancer