! ➙ " or " ➙ ! Which is a better fit in sarcoma research? Robert Maki, MD PhD Financial COI Bayer Deciphera Karyopharm Lilly / Imclone Pfizer Springworks UptoDate American Society for Clinical Oncology American Association for Cancer Research • Examples of bench ➙ bedside Outline • Muramyl tripeptide in osteosarcoma • PARP inhibitors in Ewing sarcoma (…CDK12, LSD1) • IGF1R in rhabdomyosarcoma, Ewing sarcoma • … • Examples of bedside ➙ bench • Trabectedin in myxoid-round cell liposarcoma • Defining Ewing-like sarcomas • TKI in desmoid tumor, soft tissue sarcomas • Germ line alterations in sarcoma patients (cancer patients in general) • … • Examples of convergence • Immunotherapy in sarcomas, NY-ESO-1, immune checkpoint inhibitors. • GIST • MYC amplification and chemotherapy sensitivity • Which works “better”? • In which direction will the arrow point 2020-2025? !➙ " Medical oncology: “all” bedside to bench (bootstrapping = arrancar[se]?) Goodman LS et al. JAMA 1946; 132: 126 Muramyl tripeptide (MTP): Eugenie Kleinerman Meyers PA and Chou AJ. Current Advances in Osteosarcoma. Adv Exp Med Biol., Vol 804, 2014 MTP (mifamurtide) • Synthetic derivative of BCG cell wall peptidoglycan • Serves as an adjuvant for immune responses • Encapsulating in liposomes increased macrophage uptake • Spontaneous metastases in mice eliminated with IV MDP • MTP makes human monocytes tumoricidal • Imaging of radioactive MTP: taken up in spleen, liver, lungs, nasopharynx, and occasionally tumor • Phase I: MTD 6 mg/m2: Fever, chills, malaise, nausea • Optimal biological dose defined as 0.5 – 2 mg/m2 Zwilling BS, Campolito LB. J Immunol 1977; 119: 838. PMID 330756 FiDlEr IJ et al. PNAS 1981; 78: 1680. PMID 6940181 KlEinErman ES Et al. CancEr REs 1983; 43: 2010. PMID 6831430 Murray JL Et al. JCO 1989; 7: 1915. PMID 2479721 MTP (mifamurtide) • Dog osteosarcoma model: MTP vs placebo post amputation • Median overall survival 77 d (placebo) vs 222 d (MTP) MacEwen EG et al. JNCI 1989; 81: 935. PMID 2733037 Summary data: Osteosarcoma Rx Neo/adjuvant chemo ± Ifosfamide, ± MTP Ifosfamide made no difference Mifamurtide made a difference Meyers PA et al. JCO 2008; 26: 633 ! ➙ " Trabectedin in myxoid-round cell liposarcoma (MRCLS) • Compassionate use study showed better results in in MRCLS than other sarcoma subtypes • n=51 • 2 CR, 24 PR = RR 51% • Tumor density changes seen before shrinking in patients • (Choi response in GIST) • Median PFS 14 months, 88% 6-month PFS • Differentiation induced in some tumors • Some data on mechanism of action only years later (D’Incalci) • FUS-DDIT3 translocation product dropped off promoters Grosso F et al. Lancet Oncol 2007; 8: 595 PMID 17586092 Forni C et al. Mol Cancer Ther 2009; 8: 449 PMID 19190116 Di Giandomenico S et al. Oncogene 2014; 33: 5201 PMID: 24213580 Defining Ewing-like sarcomas • Some ”translocation-negative” Ewing sarcomas did not respond well to chemotherapy • One pediatric sarcoma was seen to have CIC-DUX4 in 2009 • Identification of EWSR1-negative Ewing-like sarcomas • CIC-DUX4 < EWSR1-FLI1 outcomes • BCOR-CCNB3 > EWSR1-FLI1 outcomes • Knowledge of the fusions provides a tool for better understanding biology Yoshimoto M et al. Cancer Genet Cytogenet 2009; 195: 1 PMID 19837261 Graham C et al. Hum Pathol 2012; 43: 180 PMID 21813156 Italiano A et al. GCC 2012; 51: 207 PMID 22072439 Pierron G et al. Nat Genet 2012; 44: 461 PMID 22387997 Choi EY et al. Am J Surg Pathol 2013; 37: 1379 PMID 23887164 Puls F et al. Am J Surg Pathol 2014; 38: 1307 PMID 24805859 ! ⇆ " NY-ESO-1 in sarcoma subtypes • Hunt for genuinely tumor-specific antigens • Found in esophageal squamous cell cancer patient serological screen • NY-ESO-1 = Cancer-germ line antigen (testis, ovary) • Synovial sarcoma 1st sarcoma found with NY-ESO-1 • Later shown expressed in myxoid-round cell liposarcoma • Led to studies of NY-ESO-1 engineered T cells / CAR - T Chen YT et al. Cytogenet Cell Genet 1997; 79: 237 PMID 9605863 Jungbluth AA et al. Int J CanCer 2001; 94: 252 PMID 11668506 Segal NH et al. Cancer Immun 2005; 5: 2 PMID 15683221 PollaCk SM et al. CanCer 2012; 118: 4564 PMID: 22359263 Robbins PF et al JCO 2011; 29: 917 PMID: 21282551 D’Angelo SP et al CanCer DisCov 2018; 8: 944 PMID: 29891538 Immune checkpoint inhibitors in UPS, ASPS, angiosarcoma • SARC 28: pembrolizumab phase II • n=70, 1/10 CR, 3/10 PR on pembrolizumab, rare other PR • Alliance: nivolumab ± ipilimumab • n=86, CR in Myxofibro, ULMS; PR in UPS, LMS, angio, ASPS • GSF: Cyclophosphamide + pembrolizumab phase II • n=50 evaluable, only 1 PR (UPS) • Combination trials • PD1 and PDL1 mAb combination phase I studies • Axitinib and pembrolizumab with (mostly) ASPS responses • Why? High PD-L1 (< 5% of tumors?), TMB (only moderate) Tawbi HA et al. Lancet Oncol 2017; 18:1493 PMID 28988646 D’Angelo SP et al. Lancet Oncol. 2018; 19:416 PMID: 29370992 Toulmonde M et al. JAMA Oncol. 2018; 4:93 PMID: 28662235 Wilky BA et al. Lancet Oncol 2019, 20: 837 PMID 31078463 ”Leiomyosarcoma of the GI tract”, n=54 Diagnosed before 1975, minimum 10 years’ follow-up Evans HL. Cancer 1985; 56: 2242. PMID 4052969 W/W GIST diagnosis and treatment W/Wv • GI leiomyosarcomas (pre 1998): do not respond to chemotherapy like other leiomyosarcomas • Peritoneal, liver metastases seen • Studies of KIT in W/W mice ICC • ”W/W”: lack extracellular domain in KIT (dominant spotting) • Mast cell, melanocyte, neuronal expression altered, anemia • W/Wv “black eye/white” mice have bowel motility problems, no ICCs, other developmental problems • 1994: Mutation in KIT in mast cell leukemia GIST • 1998: Mutation in KIT in GIST • 1998: Detection of KIT mutation in familial GIST del559 Hirota S et al. Science 1998; 279: 577 PMID 9438854 Nishida T et al. Nat Genet 1998; 19: 323 PMID 9697690 Well, which works “better”? • Both are compelling ! • Moving a basic science finding to the clinic and showing its effectiveness • Many well-conceived lines of research end up with no clinically useful result • “MELK inhibitor” OTS964 is actually a CDK11B inhibitor • However, clinical observation can be useful too, cueing research in the laboratory – serendipity • In many instances, there are elements of both methodicality and observation • For the omniscient, you do not need either approach • For the rest of us, both avenues together provide the greatest chance of success for an individual patient or a group of patients as a whole Lin A et al. Sci Trans Med 2019; 11: eaaw8412 Where are we going in the next 5 years? • Greater attention to specific histologies or molecular abnormalities within histologies • New Rx / biology to pursue: • Epigenetics • Metabolism • Poisoning dependencies – lactate in ASPS, glutamine in KEAP1 mutated tumors, more on TOR? • Oxidative stress • Further exploration of kinase inhibitors (> 400 human kinase identified) • Protein acetylation, ubiquitination, and other modifications • Immunology • CAR-T for specific diagnoses – more than synovial sarcoma and M/RC liposarcoma? • Vaccine + checkpoint inhibitor • Checkpoint inhibitor + other immunostimulant • Regulation of the RNA world • Antisense Rx of miRNA, piRNA, lncRNA, MYC or other difficult to target oncogenes? • Clinical trials should aim for big / meaningful signals • For diagnoses without new agents (osteo, Ewing sarcoma) - do better with what we have • Shorter course Rx for Ewing sarcoma vs standard, e.g. - End - CONDUCCIÓN AGRESIVA ESTRICTAMENTE APLICADA In New York, aggressiveness is not just a suggestion, IT’S THE LAW! Bob Maki MD @ gmail . com.