Tak Mak

Tak Mak (Princess Margaret Cancer Centre, University Health Network, Canada)
“Beyond Targeting Oncogenes: Future Anti-Cancer Strategies”

Tak Mak (Princess Margaret Cancer Centre, University Health Network, Canada)
“Beyond Targeting Oncogenes: Future Anti-Cancer Strategies”

– 1983, Discover T cell receptor, 1995- published a landmark paper on the function of CTLA4

By the turn of the last century chemotherapeutic agents have hit the wall
1942 nitrogen mustard
1948
1966- the origin of cancer
Meeting of the nobel-laureates in June, 1966 (Linddau, Lake Constance, Germany), tried to figure out the causes of cancer! (Part I, Part 2)

• Not caused by viruses
• Not caused by genes. 
• The cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar (Otto Warburg)

Targeting oncogenes is shooting the horses

• Nat Re Drug Discovery 13, 828-851
• 50,000 patients sequenced 
• RW Weinberg: there are more paths to developing tumors than there a are starts in the sky! 多富有哲理~

Remember what Warburg also said

• Aesop fire and water
• Oxidative stress
• DNA damage
• Immune activate Redox, DNA repair , homeostasis –> metabolic adaptation

Beyond infectious diseases: the many layers of immunological research

• Autoimmune disease
• Malignancies
• Cardiovascular

Future: target the carts?
(The cart is the transformed state of the cancer cell as a consequence of the actions of oncogene and tumor suppressor genes. Carts are independent)

Lao Tsu 老子 (600BC)
Countless words count less than the silent balance between yin and yang

1974 Feb 2 Science, 183: 534
– Osias Stutman Tumor development after 3-methylcolanthrene in immunologically deficient athymic-nude mice

A village of immunologists (1970s – now)

• 1995 (Science Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4 |  lymphoprolifeartion in CTLA4/- mice)
• 2005 (Nat Rev Immunol Roles of interferon-regulatory factors in T-helper-cell differentiation / generate knockout mice of immune genes
• 2015 (Nat Rev Immuno  Regulation of tumour necrosis factor signalling: live or let die.)

Basic mechanisms of T cell stimulation and inhibition
– Siu L, Toronto ORR to anti-checkpoint antibodies in the most lethal cancers

R/R HL response to immune checkpoint blockade made is 85%!

• 1994 Poppema and Visser 
• Am J Pathol  Absence of HLA class I expression by Reed-Sternberg cells
• Cancer Epstein-Barr virus positivity in Hodgkin’s disease does not correlate with an HLA A2-negative phenotype
• 2015 Reichel J …. Roshal
• Blood Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells

Annals of Oncology 2017 (Combination partners with immunotherapy agents) rational for combinations:

1. Animal models
2. Failed drugs/bppost sales
3. Why not

T cell complexities = more drug targets.
ASCO 2106 Janet Wolchok poster checkmate 067 “phase III trial of melanoma” (Link)

Epacadpstat [;is [er,mbrolizumab versus pembrolizumab alone in [patients with unresectable pr metastatic melanoma: rsiults of the phase 3 echo-201 keynote

Anti-PDL1 + Mek inhibitor (just announced may 2018) [Roche halts enrollment in a ph II combo study of Tecetriq and Corelli in wake of several patient deaths)

2017 Immunity Glutathione Primes T Cell Metabolism for Inflammation.

• ROS-derived GSH is crucial for metabolic reprogramming of T cells Mak …Brenner, Immunity 2017
• Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses.

2010 Trends Pharmacol Sci. Fighting cancers from within: augmenting tumor immunity with cytokine therapy.
– Immune regulation in infection
– Self antigens (immunological tolerance, immune ignorance, limited T cells)
– IL7 treatment profoundly increases survival of tumor mice -> by inhibiting spontaneous T cell infiltration in tumor progression

Model: iRhome2 required for TACe maturation (Mcllwain et al Science 2012)

• iRHOM2 is a critical pathogenic mediator of inflammatory that regulates myeloid cells
• RhoC-/- (pathology
• ITAM/ITIM receptors on immune (T, B, Neu, Moni, Mi, NK) cells
• active type LILARA (6 in human and 1 in mice)
• Suppressive type LILRB (5 in human 1 in mice)
• Monocytes in wildytupe and KO of Pir-B (M2-ITIM)
•  Single cell RNA sequencing

T cell receptor (Matisse’s et al Nat Immunology 2014)

• In 8 seconds ~ 100 pathways activate! And some breaks show up
• LAT interactome
• SHIP1, E3 ligand, MAP4 kinase
• T cells will dived in 5 hours
• CTLA4

CFI-402411 synergizes strongly with anti-PD1 in the CT26 syngeneric mice

Future : metabolism

Determinants of the tumor metabolic
Interplay: ROS-redox, cell death-inflammation and cancer Nat Rev Drug Dis 2013

Examples: IDH mutations AML, cholangiocarcinoma

• AML is the type they want to study 2013 Canc er Disovery Cairns and Mak
• Both wildtype and mutant IDH1 can regulate the cytotoxic a-KG levels
• Patients with IDH mutation, D2HG do better than patient with TET2 putations
• Durable remissions with Ivosidenib in IDH1-mutated replayed refractory AML (NEJM 2018 June)

Two DNA damage checkpoints in G1 to S transition

• p16 (HNSCC 15-20% deletion; in NPC unferexpressiomn of p16 in 50-65% patients)
• MTAP Cell reports 2016 15, 574-587 (atop s doses 1st [patienmt worth MAT2A inhibitor

Aneuploidity

• NPC (p53, ATM, BRCA, PTEN -> genome unstable?).
• GI (Chen et al Oncogene 2014, Gruhne et PNAS, Chen et al BMC Cancer 2017
• Postulated development of breaks cancer Lumina A, B, TNBC
• Inhibitor s PLK4 and TTK (CFI sulk be
• Two DNA damage checkpoints in transition from G1 to S