Understanding Multi-Drug Resistance and Breast Cancer Treatments

School

University of Guelph**We aren't endorsed by this school

Course

BIOM 4090

Subject

Biology

Date

Dec 11, 2024

Pages

Uploaded by ChefLlamaPerson1300

MULTI-DRUG RESISTANCE (MDR)Enhanced efflux: expression of transmembrane protein which enhances excretion of drug from cancer cellMulti-drug resistance = efflux pump that affects several drugsMDR observed in several cancers:eg. ovarian, breast, prostate, GI tract, lung, neuroblastoma, lymphoma, leukemiaExamples of MDR proteins:Permeability glycoprotein (P-glycoprotein)MDR-associated protein (multiple sub-types) Lung-resistance proteinBreast cancer resistance protein

P-GlycoproteinAka: multi-drug resistance protein1 (MDR1) ATP-binding cassette sub-family B member 1 (ABCB1) cluster of differentiation 243 (CD243)170 KDa transmembrane ATP-binding transporter expressed in: intestinal epithelium hepatocytes pancreatic cells renal tubule cells capillary endothelial cells (eg. blood brain barrier)Protects cells against toxins but increased expression in tumour cells interferes with many chemotherapeutic agents

ATP & drug bind ATP hydrolysis releases phosphate to shift position of drug →excretionIn some cancer cells:Estrogen downregulates protein expression of P-glycoprotein Tamoxifen –inhibits efflux of some drugs by P-glycoproteinCisplatin or doxorubicin can induce P-glycoprotein expression

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancerSyedet al. Scientific Reportsvolume 7, Article number: 7972 (2017)

TREATMENT OF BREAST CANCER~13 % of women develop breast cancer~3 % of women will die of breast cancerMany types/stagesTumours are heterogeneousTreatment optionsSurgeryRadiation TherapyCytotoxic ChemotherapyHormone TherapyTargeted TherapyComplementary & Holistic Medicine

TYPES & GRADESMost CommonDuctal: inside milk duct (in situ or invasive)Lobular: inside milk-producing gland (in situ or invasive)RareInflammatory breast cancerMale breast cancerGradeDescriptionILow-grade (well-differentiated) tumours that do not appear to be growing quickly and are less likely to spreadIIIntermediate-grade (moderately differentiated) tumours that have features between grade 1 and 3IIIHigh-grade (poorly differentiated or undifferentiated) tumours that tend to grow faster and are more likely to spread

TREATMENT OF BREAST CANCERSTAGE I - surgerySTAGE II no lymph node involvement –surgery & radiationSTAGE II with lymph node involvement (less than 4) surgery &/or radiation and chemotherapySeveral chemotherapy combinations (see next slide)Hormone sensitive tumors: ER positive –tamoxifen/ anastrozoleProgesterone receptor (PR) positiveHER-2 positive –antibodies/HER-2 receptor antagonists

TREATMENT OF BREAST CANCERStage III and IV –treatment options often considered palliative rather than curative –some women live several years with metastatic breast cancerExamples of traditional chemotherapy combinations:cyclophosphamide & doxorubicincyclophosphamide, methotrexate & 5-fluorouracilcyclophosphamide, paclitaxel & doxorubicincyclophosphamide, 5-fluorouracil & doxorubicincyclophosphamide, methotrexate, 5-fluorouracil, prednisone & vincristine

Strong Case for Weekly Paclitaxel in Breast Cancer by Nick Mulcahy, Chicago 2013 The 2 commonly used schedules were equally effective in women with high-risk stage I to III breast cancer, report lead study author G. Thomas Budd, MD, from the Cleveland Clinic in Ohio, and colleagues.In the Southwest Oncology Group (SWOG) S0221 trial, estimated 5-year progression-free survival rates were equivalent for paclitaxel administered weekly (82%) and paclitaxel administered every 2 weeks (81%).However, the low-dose weekly schedule was significantly less toxic than the dose-dense biweekly schedule for neurologic events (17% vs 10%; P < .001) and musculoskeletal pain (11% vs 3%; P < .001).

TARGETED THERAPYTrastuzumab(Herceptin)Approved for HER2 overexpressing breast cancerHerceptin + paclitaxel is first line treatment of HER2 over-expressing metastatic breast cancerAntibody –acts as antagonist of HER2 receptorwww.roche.com

TARGETED THERAPYBevacizumab(Avastin)Approved by FDA in 2008 for use in combination with paclitaxel for metastatic breast cancer but withdrawn in 2011. Approved for some metastatic cancers (ovarian, kidney, colon and lung).Angiogenesis inhibitorAntibody –binds VEGF and acts as antagonist of VEGFR2www.molecularonc.comVEGF= vascular endothelial growth factorVEGFR2 = VEGF receptor

ADVERSE EFFECTSTrastuzumabFever, aches, chills, nausea and diarrheaCardiac dysfunction, including congestive heart failure (downregulates expression of neuregulin 1 which is involved in the activation of cell survival pathways in cardiac myocytes)BevacizumabInhibition of blood vessel growth for maintenance and healingHypertension, bleeding

http://www.parp-inhibitors.com/OLAPARIB

OlaparibOrally administered poly ADP ribose polymerase (PARP) inhibitorFDA approved 2018: metastatic, HER2-negative breast cancer with BRCA gene mutation and have already had chemotherapy.(Approved in 2014 for BRCA mutated advanced ovarian cancer) Adverse effects -bone marrow suppression-GI disturbances (nausea, vomiting), anorexia-fatigue-muscle and joint painTARGETED THERAPY

AtezolizumabMonoclonal antibody against the programmed cell death-ligand 1 (PD-L1) protein; administered by slow IV infusion (every 2 to 4 weeks)FDA approved 2019: triple-negative breast cancer (does not express ER, PR and HER2) (Previously approved for some advanced, resistant and/or high PD-L1 expressing lung, bladder & liver cancers)Adverse effects - nausea, anorexia-fatigue-urinary tract infectionIMMUNOTHERAPY