Colorectal Cancers Study Presentation

f Colorectal Cancers Gauri Sabnis, PhD 3rdmostcancerinUrsfor BothaandI Recommended Reading: Katzung et al, Basic and Clinical Pharmacology, Chapter 54 Dipiro et al, Pharmacotherapy: A pathophysiologic Approach, Chapter 107 https://www.cancer.gov/types/colorectal 1 Transverse colon Left colic (splenic) flexure Right colic (hepatic) flexure Descending colon Ascending colon Omental appendices Teniae coli Ileum Mesoappendix Ileocecal sphincter (valve) Haustra opt Sigmoid colon Cecum Rectum Vermiform appendix Anal canal Anus Anterior view of large intestine showing major regions 4 Risk factors Benigngrowththatdevelopsontle Liningofthecoonovredum no ✥Prior history of adenomatous polyps or colorectal cancer ✥Inflammatory bowel disease And ✥Type 2 DM age ✥Obesity, being overweight ✥Sedentary lifestyle ✥Alcohol intake food morepress ✥Smoking ✥Western dietmom Mahany ✥Reduced risk ❊Aspirin and NSAID use Triska ❊Postmenopausal HRT ragtag ❊Calcium and vitamin D intake 5 Genetic mutations associated with colorectal cancers ✥Germline ❊ Familial adenomatous polyposis (FAP) ⇥ Mutations in the APC gene – autosomal dominant ⇥ MYH-associated polyposis –autosomal recessive ⇥ Frequent K-Ras mutation ❊ Hereditary non-polyposis colorectal cancer – DNA MMR genes (MLH1, MSH2, MSH6, PMS2) ⇥ Familial cancer predisposition (Lynch syndrome) ✥Somatic ❊ Sporadic colorectal cancer • Majority of colorectal cancers are sporadic ⇥ Oncogene activation – K-Ras, B-Raf, EGFR, PIK3CA ⇥ Loss of tumor suppressor – p53, PTEN so *NLM-Genetics Home Reference 7 Prevention Strategies ✥High fiber diet ✥Green tea polyphenols ✥Curcumin (turmeric) ✥Omega-3-PUFAs ✥Probiotic bacteria No conclusive data ✥Statins ✥Metformin ✥Calcium, vitamin D ✥Aspirin, NSAIDs and COX-2 inhibitors 8 Symptoms ✥A change in bowel habits ✥Blood in the stool (bright red or very dark) ❊ Most common sign ❊ Anemia due to blood loss ✥Diarrhea, constipation, or feeling that the bowel does not empty all the way, stools that are narrower than usual ✥Frequent gas pains, bloating, fullness, or cramps ✥Weight loss for no known reason ✥Fatigue ✥Vomiting ✥Fistula formation ✥Pain in the lower back radiating down the leg – Stage IV disease 9 FOBT Colorectal cancer screening ✥Digital rectal exam ✥Fecal occult blood test (FOBT) ❊ Guaiac FOBT ❊ Immunochemical FOBT ✥Imaging ❊ Barium enema not ❊ Sigmoidoscopyas ❊ Colonoscopy Dignam Notthefulloton semicolon justshow ❊ Virtual colonoscopy growth the inside ✥Diagnosis - Biopsy ✥Blood test — CEA (carcinoembryonic antigen) ❊ Tracked over time for prognosis, recurrence, Rx response 10 Patient counseling for FOBT ✥To avoid false positive ❊ Dietary restrictions ⇥ Avoid red meat ⇥ Raw vegetables with peroxidase activity (turnips, broccoli, cauliflower etc. for 3 days prior) ❊ Medical restrictions ✥To avoid false negatives ❊ Avoid vitamin C in excess of 250 mg from supplements and fruit or juices for 3 days prior ❊ Avoid testing dehydrated sample ⇥ Avoid rectal enemas, rectal medications, digital rectal exams for 3 days prior ⇥ Avoid aspirin, NSAIDs for up to 7 days prior ⇥ Avoid testing if blood from hemorrhoids is evident ⇥ Delay testing until 3 days after menstruation 11 Treatment ✥Surgery By ❊ Complete resection with 5 cm margin ❊ Sparing OR permanent sigmoid colostomy ✥Radiation Sunday ❊ Palliative for advanced disease ❊ Curative for local demo category control ✥Adjuvant chemotherapy ❊ Cytotoxic chemotherapy ❊ Targeted therapy ❊ Immunotherapy 13 Pharmacotherapy ✥Adjuvant cytotoxic chemotherapy ❊ Preferred agents for CRC - 5-FU, oxaliplatin and irinotecan ⇥FOLFOX4 ⇥mFOLFOX6 ⇥FLOX ⇥Capecitabine ⇥CAPEOX ⇥FOLFIRI ⇥FOLFOXIRI ⇥IROX ✥Targeted therapy (requires screening) ❊ Bevacizumab, regorafenib — Angiogenesis targeting ❊ Cetuximab, panitumumab —EGFR targeted (KRAS and NRAS wt only) ❊ Vemurafenib (B-Raf V600E mutations or KRAS, NRAS mutations) ✥Immunotherapy ❊ Nivolumab ± ipilimumab OR pembrolizumab (MMR or MSI-H testing) 14 1 Antimetabolites ✥Compounds related to normal components of the DNA or coenzymes required for nucleic acid synthesis ✥Competitively inhibit utilization of normal substrate and get incorporated in the DNA forming dysfunctional macromolecules ✥Block enzyme activity responsible for generating normal substrates ❊ Folate Antagonists ⇥ Methotrexate ❊ Purine antagonists ⇥ 6-mercaptopurine, 6-thioguanine ❊ Pyrimidine antagonists ⇥ 5-flurouracil, capecitabine, gemcitabine ❊ Ribonucleotide reductase inhibitors ⇥ Hydroxyurea ✥Major ADRs of this class include – myelosuppression, GI toxicity (mucositis/stomatitis, diarrhea) and most also TLS (hyperuricemia) 15 ✥Ribonucleotide reductase Antimetabolite Targets ❊ Hydroxyurea ❊ Fludarabine ❊ Cytarabine ❊ Clofarabine ❊ Gemcitabine Pyrimidine synthesis ✥Dihydrofolate reductase (DHFR) (also needed for purine synthesis) Aspartate Hydroxyurea Fludarabine Carbamoyl phosphate Orotate RNA PRPP UMP Ribonucleotide reductase CTP UTP Ribonucleotide reductase dUMP Thymidylate 5-FU synthase Pemetrexed THF dTMP DHF DHFR MTX Pemetrexed dTTP MTHF dCTP DNA ❊ Methotrexate ❊ Pemetrexed ✥Thymidylate synthase ❊ 5-FU ❊ Pemetrexed ❊ Methotrexate ❊ Capecitabine ✥DNA polymerase ❊ 5-Azacytidine DNA ❊ Cytarabine, fludarabine, gemcitabine 16 Antimetabolite Targets Purine synthesis Pemetrexed 5-FU M-FH4 FH4 RNA GTP MTX Pemetrexed GMP Ribonucleotide reductase Hydroxyurea Fludarabine DHFR dGMP XMP Thymidylate synthase PRPP 5 step process FH2 ATP IMP dehydrogenase (IMPDH) Inosine Monophosphate (IMP) as Adenyol succinate RNA AMP Ribonucleotide reductase dAMP dGTP dATP DNA DNA 17 I to ta thiomap F fuderabin Antimetabolites (Analogs of nucleobases) Cytidine 5-Azacytidine Thymine Uracil Guanine 6-TG O Adenine Deoxyribose Fludarabine e Cytarabine† Capecitabine * 6-MP * One O Fludarabine Capecitabine 5-FU * Modification to deoxyribose present; †No modification to the nucleobase (cytosine) * Gemcitabine† 18 ✥Folic acid analog Folate antagonists – Methotrexate ❊ Acts by inhibiting dihydrofolate reductase (DHFRase) thus blocking conversion of dihydrofolate (DHF) to tetrahydrofolate (THF) Pyrimidine synthesis ⇥ Pseudo-irreversible because MTX has ~50,000-fold higher affinity for DHFRase than DHF Aspartate ⇥ Feedback inhibition of thymidylate synthase Carbamoyl phosphate Orotate RNA PRPP UMP Ribonucleotide reductase M-FH4 FH4 DHFR dUMP Thymidylate synthase FH2 dTMP MTX Pemetrexed dTTP UTP CTP Ribonucleotide reductase dCTP ✥Mechanisms of resistance ❊ Impaired transport of MTX into the cells ❊ Altered form of DHFR that has decreased affinity for MTX ❊ Increased expression of DHFR through gene amplification or altered gene regulation ❊ Decreased ability to produce MTX DNA polyglutamate ❊ Increased expression of drug efflux transporters DNA 19 comeBack Methotrexate ✥Polar in nature; does not cross BBB and need special transporter to enter cells ❊ Enters the cell using folate carrier ❊ Carrier highly expressed on hyperdiploid ALL, which is highly sensitive to MTX ❊ High dose MTX permits entry in transporter deficit cells ✥Once MTX enters the cells, additional glutamyl residues added by enzyme folylpolyglutamate synthase ❊ Addition of glutamate increases polarity and MTX is trapped in the cell ❊ Polyglutamyl MTX has higher affinity for DHFR than monoglutamyl MTX ❊ Also reason for MTX getting trapped in fluid filled cavities – 3rd space ⇥ Ascites, pleural effusions ⇥ Chorionic epithelium– Category X – abortifacient (choriocarcinoma, molar pregnancy) ✥Given as IV or PO (<25 mg/m2 absorbed well, higher doses IV) ❊ For efficacy against cancers in the brain  IT administration or high dose MTX ✥PP bound 50% ❊ Salicylates and warfarin can increase toxicity by displacing from PP es ✥Largely excreted unchanged in urine via glomerular filtration and tubular secretion ❊ Aspirin, penicillins (and cephalosporins) ❊ Drugs that are nephrotoxic can increase toxicity – NSAIDs, cisplatin etc. 20 Methotrexate and Leucovorin ✥Toxicity: Myelosuppression, and intestinal epithelium (mucositis, T diarrhea), alopecia nephrotoxicity and many more (BBWs) ❊ Can not be overcome by administering folic acid ❊ Can be overcome by administering thymidine or reduced folate leucovorin (L-leucovorin*) ⇥ Accidental overdose and rescue for high dose MTX therapy ❊ Glucarpidase for renally impaired ✥Neurotoxicity (for IT)  seizures, coma; can’t be overcome by e leucovorin Folic acid Methotrexate Folinic acid (Leucovorin) 21 ti mucositisondall It smudssupression we q j Mylo suppression Pemetrexed (Alimta) who ✥Similar to MTX, but considered a multi-target folate analog ❊ Inhibit DHFRase but mainly thymidylate synthase (TS) is ❊ Transport across RFC1 plateaus with MTX but not with pemetrexed (2X affinity over MTX); 2nd carrier takes over if RFC1-based uptake is impaired ⇥ Undergoes polyglutamation and gets trapped ✥Minimally metabolized and excreted in urine unchanged ✥Toxicities: myelosuppression, mucositis, diarrhea, skin rash, hand-foot syndrome ❊ Vitamin supplementation with B9 and B12 is must to reduce toxicity 22 sulfurcontaingandogs Ribose-5’-phosphate WE Purine antagonists – 6-thiopurines HGPRT ✥Mercaptopurine (6-MP) and Active thiopurine ribonucleotide 6-Thioinosic acid (R = H) 6-Thioguanylic acid (R = NH2) TPMT TPMT Thiopurine Prodrug 6-MP (R = H) 6-TG (R = NH2) thioguanine (6-TG) ❊ Thiol analogs of endogenous purines ❊ Prodrugs that need to get converted Active S-Methyl-thiopurine ribonucleotide (R = H) ⇥ Hypoxanthine guanine phosphoribosyl transferase (HGPRT) ✥After getting converted to respective monoribonucleotides, inhibit conversion of IMP to AMP and GMP Inactive S-Methyl-6-MP (R = H) S-Methyl-6-TG (R = NH2) ❊ Get incorporated into the DNA and RNA ✥Metabolized by thiopurine methyl transferase (TPMT) ❊ Patients who have pharmacogenomic Guanine 6-TG 6-MP Adenine deficiency of this enzyme may develop severe toxicity 23 ✥Toxicities: myelosuppression 6-thiopurines (slowly), nausea and vomiting (6-MP>6-TG), hyperuricemia ✥6-TG undergoes deamination (not impacted by allopurinol) HGPRT ❊Allopurinol – hyperuricemia supportive care Mercaptopurine Xanthine oxidase ❊Combined use – reduce dose of 6- MP by 50-75% my Allopurinol Guanase Adjust 6-Thioinosic acid (Active) Dgse ✥TPMT deficiency  severe tox ⇥ Myelosuppression ⇥ GI- mucositis and diarrhea Xanthine oxidase 6-Thioxanthine (Inactive) 6 - Thiouric acid (Inactive) Allopurinol 24 Fludarabine ✥Newer antimetabolite purine rapidly gets dephosphrylated to 2fluoro-arabinofuranosyladenosine and transported into the cell where it gets phosphorylated by deoxycytidine kinase to monophosphate and eventually to triphosphate ❊ Triphosphate t Mayone ⇥ Inhibits DNA polymerase ⇥ Gets incorporated to form dysfunctional DNA and interferes with DNA repair ❊ Diphosphate form ⇥ Blocks ribonucleotide reductase ❊ Induces apoptosis ❊ Active even in slower growing tumors ✥Toxicities: myelosuppression, and opportunistic infections; fever, chills, myalgia, arthralgia after injection AD by 25 Pyrimidine antagonists – Fluoropyrimidines ✥Analogs of uracil ❊ 5-FU is inactive in its parent form gets activated in the tumors ❊ Capecitabine (Xeloda) is a carbamate prodrug of 5-FU that is orally active ✥Major toxicities: myelosuppression, GI, dermatologic ✥P’genomics: DPD deficiency Uracil 5-FU Capecitabine 26 ✥5-flurouracil (5-FU) converted to nucleotide (FdUMP) ✥Forms a covalent ternary complex with MTHF and thymidylate synthase (TS) and irreversible inhibition of TS 5-FU activation ❊ Unavailability of thymidylate  Failure of DNA synthesis --> “thymineless death” Orotate phosphoribosyltransferase ✥5-FU is also converted to 5-FUTP, which is incorporated in the RNA and FdUTP which gets incorporated in DNA 5-FU 5-F UMP (Prodrug) UMP kinase ❊ Combined effect on DNA and RNA ✥Short t½ of 10-15 minutes (infusion) ✥80-85% of the dose is metabolized by dihydropyrimidine dehydrogenase (DPD). Ribonucleotide reductase 5-F-dUDP ❊ Genetic syndrome with complete or partial 5-F UDP Phosphatase deficiency of DPD  severe toxicity (myelosuppression, diarrhea, nausea, vomiting and neurotoxicity) ✥Leucovorin stabilizes the 5-FU and TS complex  increase toxicity 2’-Deoxyuridine kinase 5F-dUMP (Active Form) ✥Toxicities: myelosuppression, mucositis, Floxuridine (Prodrug) diarrhea, skin (hand-foot syndrome) and neurotoxicity 27 ✥Fluropyrimidine carbamate prodrug Capecitabine of 5-FU, undergoes metabolic activation to deoxycytidine (active PO) ❊ First 2 reactions in the liver ❊ Conversion to 5-FU in the tumor ⇥ Expression of thymidine phosphorylase is higher in cancer cells (breast and colon) compared to normal cells Carboxyesterase ✥Hand-foot syndrome and diarrhea are Capecitabine frequent side effects (Prodrug) 5’-DFCR Cytidine deaminase 5-FU ✥Other ADRs – myelosuppression, CINV, mucositis, and alopecia observed but much lower than 5-FU ✥BBW: Warfarin interaction (especially Thymidine phosphorylase if >60 YO) - Orotate PR-transferase - UMP kinase - Ribonucleotide reductase - Phosphatase ✥DDI – Avoid concomitant PPIs  reduced absorption 5F-dUMP (Active Form) 5’-DFUR 28 Pyrimidine Analogs – deoxycytidine analogs Cytidine 5-Azacytidine Cytarabine Gemcitabine Cytosine arabinoside/Ara C ✥Incorporates into DNA and RNA ❊ Prevents elongation of chain ❊ Inhibitor of DNA polymerase ❊ Inhibit DNMT (azacytidine) 29 ✥Converted to 5’-mononucleotide and Cytarabine further to diphosphate and then triphosphate ❊ Ara-CTP (active) inhibits DNA polymerase and thus synthesis and repair ❊ Interferes with both DNA and RNA Deoxycytidine kinase ✥Rapidly cleared due to inactivation into deamidated from ❊ Administered as CIV; also given IT ✥Toxicity: myelosuppression, mucositis, Cytarabine Ara-cytidine monophosphate (Cytosine arabinoside) Deoxycytidine deaminase Pyrimidine mono and diphosphate kinase NV (dose), diarrhea, TLS ❊ Cytarabine syndrome: fever, myalgias, rash, conjunctivitis ✥No activity in solid tumors ❊ Only hematologic malignancies thiamineonlyinterferewi Uracil arabinoside (R=H) Uracil arabinotide (R=PH2O3) (Inactive) Ara-cytidine triphosphate (Active Form) DIA andRIA otheragentsBothDNA 30 Gemcitabine ✥Activated similar to cytarabine but unlike cytarabine active in solid tumors ❊ Inhibits ribonucleotide reductase – diphosphate form ❊ Inhibits DNA polymerase – triphosphate form ⇥ Blocking DNA synthesis and repair ❊ Gets incorporated in DNA ✥Toxicities: myelosuppression, capillary leak syndrome, hemolytic uremic syndrome (HUS), hepatotoxicity, posterior reversible encephalopathy (PRES) Go reversiblebrain swelling 31 Summary of Antimetabolites ✥Folate analogs/antagonists ❊ Methotrexate and pemetrexed ✥Purine analogs ❊ 6 – mercaptopurine, 6 – thioguanine (S in the nucleobase) ❊ Fludarabine, clofarabine (fluorine in the nucleobase; presence of deoxyribose) ✥Pyrimidine analogs ❊ 5-FU (F in nucleobase); floxuridine (5-FU w/deoxyribose); capecitabine (prodrug of 5-FU; contains deoxyribose) ❊ Cytarabine (cytosine with deoxyribose); gemcitabine (fluoridated deoxyribose) ❊ azacytidine (cytidine with additional N) ✥All active in S-phase of cell cycle ✥Main toxicities – myelosuppression, GI tox and hyperuricemia (most) ✥PO activity – MTX, 6-MP, 6-TG, Capecitabine ✥Can give IT – MTX, cytarabine Intrathecal 32 4 Topoisomerase Poisons ✥Topoisomerase enzymes ❊ Control the degree of DNA supercoiling to maintain proper DNA structure during replication and transcription ❊ Through trans-esterification of tyrosine residues and then reverse trans-esterification they repair their own damage ✥Topoisomerase I ❊ Reduces DNA supercoiling by inducing ss breaks, re-ligates the DNA ✥Topoisomerase II ❊ Reduces DNA supercoiling by inducing ds breaks and religates the breaks ✥Topoisomerase poisons allow the breaking of the DNA strand, but prevent the re-ligation step leaving DNA strand(s) broken —irreversible DNA damage ✥Topo-I inhibitors – Camptothecins  Topotecan, irinotecan ✥Topo-II inhibitors – Epipodophyllotoxins  Etoposide, teniposide 33 Camptothecins ✥Irinotecan —water soluble prodrug, cleaved by carboxyesterase to release lipophilic metabolite SN-38 (also metabolized by CYP3A4) ❊ 100X more active ❊ Has a t½ 2X than that of irinotecan ❊ Highly protein bound (~95%) ✥SN-38 is metabolized by enzyme UDP-glucuronosyl transferase (UGT)A1 ❊ Patients with deficiency of (UGT)A1 unable to metabolize SN-38 and exhibit excessive toxicity (myelosuppression - BBW) ❊ ~10% of patients have homozygous UGT(A1) deficiency ✥Irinotecan also inhibits acetylcholinesterase (AChE) leading to cholinergic acute effects ❊ Lacrimation, rhinorrhea, diarrhea, sweating, flushing ❊ Prior atropinization ✥Diarrhea (acute - ACh effect) can also be delayed - can be fatal (BBW) ❊ Loperamide 5 ✥Irinotecan - liposomal formulation - DO NOT substitute ✥Topotecan —less diarrhea, no SN-38, not UGT(A1) issue, also available as PO 34 Camptothecins ✥Semisynthetic compounds derived from alkaloid extracts of bark of Camptotheca acuminata tree (China) – Happy tree ❊ Irinotecan ❊ Topotecan ✥Inhibit Topo I leading to DNA damage ✥Stabilize Topo I-nicked DNA complex and prevent relegation Topotecan ❊ Binding pocket for the drugs in only revealed after the Topo-I has already nicked the DNA ✥These agents are more specific to cells in S-phase of cell cycle Irinotecan 35 ✥Water soluble prodrug, cleaved by Irinotecan carboxyesterase to release lipophilic metabolite SN-38 (also metabolized by CYP3A4) ❊ 100X more active ❊ Has a t½ 2X than that of irinotecan ❊ Highly protein bound (~95%) ✥SN-38 is metabolized by enzyme UDPglucuronosyl transferase (UGT)A1 ❊ Patients with deficiency of (UGT)A1 unable to metabolize SN-38 and exhibit excessive toxicity (myelosuppression - BBW) ❊ ~10% of patients have homozygous UGT(A1) deficiency ❊ CYP3A4 mediated DDI/DFI ✥Irinotecan also inhibits acetylcholinesterase (AChE) leading to cholinergic acute effects ❊ Lacrimation, rhinorrhea, diarrhea, sweating, flushing ❊ Prior atropinization ✥Diarrhea (acute - ACh effect) can also be delayed - can be fatal (BBW) ❊ Loperamide ✥Other tox: myelosuppression (BBW), alopecia ✥Irinotecan - liposomal formulation - DO NOT substitute 36 Topotecan ✥Has less diarrhea, no SN-38, not UGT(A1) issue, also PO bioavailability ✥CYP3A4 DDIs ✥Toxicities: ❊ Myelosuppression, GI toxicity ✥IV doses should not exceed 4 mg in adults ❊ Do NOT skip the leading zero 37 ✥Etoposide, teniposide — Epipodophyllotoxins semisynthetic derivatives of podophyllotoxin, a plant glycoside from mayapple tree (Podophyllum peltatum) ✥Inhibits topoisomerase II ❊ Causing ds breaks (preventing resealing) ❊ Acts in S-phase and early G2 phase DNA effect ❊ Can also act in G1 phase transcription inhibition effect ⇥ Administered over days ✥ADRs: myelosuppression (BBW), alopecia, dermatologic toxicity, hypotension (infusion-related), alcohol intoxication (etoposide has 33% EtOH) 38 Epipodophyllotoxins ✥Etoposide, teniposide — semisynthetic derivatives of podophyllotoxin, a plant glycoside from mayapple tree (Podophyllum peltatum) ✥Inhibits topoisomerase II ❊ Causing ds breaks (preventing resealing) ❊ Acts in S-phase and early G2 phase - DNA effect ❊ Can also act in G1 phase - transcription inhibition effect ⇥ Administered over days ✥Both available IV and PO ❊ Highly lipophilic - teniposide is more lipophilic - 2X potent ❊ Oral F is ½ so dose 2X (teniposide) ❊ Requires solubilizers for IV formulation Polysorbate (80 tween) for etoposide and Cremophor for teniposide ⇥ ⇥ Not compatible with PVC tubing Hypersensitivity reactions towards the solubalizers ❊ Teniposide spontaneously precipitates if agitated ⇥ Inline filters required to avoid precipitate from blocking lines, check lines if infusing over 24 hours ✥Toxicity: myelosuppression, alopecia, other dermatologic toxicity, hypotension ✥CYP3A4 metabolism (DDI/DFI) ✥About 50% cleared renally ❊ Dose reduction if CrCL<50ml/min ❊ If combined with nephrotoxic agents (cisplatin) 39 ✥Both available IV and PO Epipodophyllotoxins ❊ Highly lipophilic - teniposide is more lipophilic - 2X potent ❊ Oral F is ½ so dose 2X (teniposide) ❊ Requires solubilizers for IV formulation Polysorbate (80 tween) for etoposide and Kolliphor for teniposide ⇥ Hypersensitivity reactions towards the solubalizers ⇥ Not compatible with PVC tubing ❊ Teniposide spontaneously precipitates if agitated ❊ Etoposide concentration of >0.4 mg/mL very unstable ⇥ Inline filters required to avoid precipitate from blocking lines, check lines if infusing over 24 hours ✥CYP3A4 metabolism (DDI/DFI) ✥About 50% cleared renally ❊ Dose reduction if CrCL<50 mL/min ❊ If combined with nephrotoxic agents (cisplatin) 40 Other ✥Hydroxyurea ❊ Inhibits ribonucleotide reductase and prevents conversion of ribonucleotides to deoxyribonucleatides ❊ S-phase specific ❊ TLS ❊ BBW: myelosuppression and secondary malignancy 41 Cell Cycle Specific Cell cycle Non-specific Purine Analogs 6-MP 6-TG Fludarabine Antimetabolites S-phase Pyrimidine Anlaogs Capecitabine Clofarabine Cytarabine 5-FU Gemcitabine Nitrogen mustards Mechlorethamine, Melphalan Chlorambucil Cyclophosphamide, Ifosfamide Alkylating agents Triazines Thio-TEPA Folate analogs Methotrexate Pemetrexed Alkyl sulfonate Busulfan Ribonucleotide reductase inhibitor Hydroxyurea G2-M phase Topoisomerase I inhibitors Camptothecins Irinotecan Topotecan Anticancer antibiotics Bleomycin Microtubule Poisons M-phase Mitotic Spindle Poison Late G1 - S phase Topoisomerase II inhibitors Taxanes Paclitaxel Docetaxel Cabazitaxel Albraxane Vinca alkaloids Vincristine Vinblastine Vinorelbine Nitrosureas CCNU, BCNU Anthracyclines Doxorubicin Daunorubicin Epirubicin Idarubicin Mioxantrone Anticancer antibiotics Actinomycin D Mitomycin Organoplatinum compounds Cisplatin Carboplatin Oxalliplatin Epipodophyllotoxins (Etoposide, teniposide) 42 Testing of tumors before initiating therapy ✥All patients must be tested for KRAS, NRAS and BRAF mutations ❊ KRAS and/or NRAS mutations — cetuximab and panitumumab ineffective test ✥All patients must be tested for micro satellite instability (MSI) or Mismatch Repair (MMR) as ❊ MSI-H patients will not benefit from 5-FU based cytotoxic chemotherapy but respond very well to immunotherapy (w/ checkpoint inhibitors) ✥Targeted therapy (mabs) given with cytotoxic chemotherapy — immunotherapy given without cytotoxic chemotherapy 43 Immunotherapy ✥Hereditary non-polyposis colorectal cancer – ❊DNA MMR genes (MLH1, MSH2, MSH6, PMS2) ⇥ Familial cancer predisposition (Lynch syndrome) ⇥ Right sided colon cancer tumors tend to respond better ✥Cancers that are considered MSI-H are treated with immune checkpoint inhibitors ❊ Anti-CTLA-4 antibody ⇥ Ipilimumab ❊ Anti-PD-1 antibodies ⇥ Nivolumab ⇥ Pembrolizumab ❊ PD-L1 antibodies are not indicated for colon cancer (not yet) 44 MHC TCR Signal 1 Phagocytotic vesicle Amplification of Signal MHC TCR CTLA-4 Signal 1 to cell surface Amplification of Signal CD28 CD80 or CD86 Dendritic Cell (APC) Resting T cell A d te a iv ct Tc Dendritic Cell (APC) s ell Phagocytotic vesicle CTLA4 Ipilimumab NO Dampening of T cell Attack the cancer cells 45 Cancer cells evade T-cells by expressing PD-L1 on their surface MHC TCR Signal 1 Phagocytotic vesicle Phagocytotic vesicle Signal 1 Amplification of Signal CD28 CD80 or CD86 Dendritic Cell (APC) Trafficking of T-cells periphery tissues Dampening of Signal PD-L1 PD-1 Resting T cell Muted T cell Activated T-cells arrive at location Phagocytotic vesicle PD-L1 Signal 1 Dampening of Signal PD-1 Pembrolizumab Antigen-activated T cell Nivolumab 46 ✥Cetuximab (Erbitux) Brash DidBetter EGFR Targeting Antibodies ❊ Monoclonal antibody against extracellular domain of EGFR ❊ G1 type antibody - also elicits anti-tumor immune response ❊ Approved for colon cancer Rx with wt EGFR ⇥ Level of expression not indicative of response (unlike Her-2) ⇥ Ras or Raf mutations - contraindicated ❊ IgG1 type antibody - also elicits anti-tumor immune response ✥ADRs: ❊ Dermatologic toxicity (acneiform rash) ⇥ Generally reversible ⇥ Correlates w/ Rx response† ❊ Hypomagnesemia (Mg wasting) ⇥ Monitor Mg, Ca and K during Rx and at least 8 weeks after ❊ BBWs: ⇥ Infusion site reactions (premedicate with H1RA - IV 30-60 min before 1st dose) ⇥ Cardiopulmonary arrest (monitor electrolytes, caution in pts. w/ CVD) ✥Panitumumab (Vectibix) - IgG2 type ❊ BBW: Dermatologic toxicity ❊ AE: Diarrhea, mucositis ↑ when combined w/ chemo, Mg wasting and infusion reactions ❊ Ocular toxicity (keratitis, corneal perforations), †Cunningham pulmonary toxicity et al., N Engl J Med. 2004 Jul 22;351(4):337-45 47 EGFR targeting agents Cetuximab Panitumumab Necitumumab EGF, TGFα Epiregulin etc. Colon cancer indications Neuregulin No Ligands NRG-1 (NRG-1) Extracellular: Ligand Binding Domain Intracellular: P P P P Her-1 EGFR ErbB-1 P P P P P P Her-2 ErbB-2 Erlotinib Afatinib Gefitinib Osimertinib Her-3 ErbB-3 P P Tyrosine Kinase Domain Her-4 ErbB-4 48 Metastasis ✥About 20% of patients with CRC present with metastasis ✥Preferred site of metastasis ❊Liver ❊Thoracic cavity (lung, chest wall, pleura) ❊Peritoneum ❊Rarer- other GI, nervous system, bone 49