qpharm presentation pfkfb3
TRANSCRIPT
PFKFB3 inhibitors Quantum Age LLC
PFKFB3 projectbackground
A novel, best in class cancer metabolism inhibitor
Novel MoA: PFKFB3 inhibition to target cancer glycolysis
Highly selective, potent, small molecule IND candidate
Designed using proprietary molecular modeling platform
In vivo efficacy in several tumors (<20mg/kg)
Good ADMET, 30 day chronic tox. study completed
Potent backup molecules
Seeking development partner to progress into clinical trials
Targeting cancer metabolism isnot new
Methotrexate: inhibits folate metabolism
5-FU: inhibits dTMP metabolism
L-asparaginase: inhibits asparagine metabolism
New, rationally designed cancer metabolism programs are demonstrating clinical success
AGIOS
AG-221: First-in-class, oral, potent, IDH2 mutant inhibitor
Data from ongoing Phase 1 study in advanced hematologic malignancies:
§ AACR in April marked first time AG-221 data were presented in a medical forum
- Clear proof-of-concept
§ EHA data in June showed durability of response for the first time in this devastating disease
AG-120: First-in-class, oral, potent, IDH1 mutant inhibitor
Data from ongoing Phase 1 study in advanced hematologic malignancies:
§ EORTC-NCI-AACR marked first time AG-120 data presented in a medical forum
- Clear proof-of-concept
More details on the case http://tinyurl.com/kf7fbqs
PFKFB3 is a key regulator of glycolytic flux and is highly expressed and activated in most tumors
Glycolysis is a hallmark of cancer, glucose metabolism is used as a key cancer diagnostic
FDG-PET may be a useful tool for patient stratification/ efficacy assessment
- Glycolysis activation reduces reliance on mitochondria, helping cells avoid apoptosis
- Malignant, rapidly growing cells typically have glycolytic rates that are up to 200 times higher than normal
- Glycolytic phenotype correlates with cancer aggressiveness, metastasis and drug resistance
Glycolysis inhibitors may have multipleanti-cancer effects
- anti-glycolytic- anti-angiogenic- immunological
Therapeutic
potential
Silencing PFKFB3 impairs angiogenesis
PFKFB3 drives new vessel sprouting by up-regulating glycolysis in proliferating endothelial cells.
PFKFB3 silencing impairs tip cell activity and new vessel growth
Cell. 2013 Aug 1;154(3):651-63
- Proliferating stalk endothelial cells rely on glycolysis rather than oxidative phosphorylation for ATP production
- Silencing the glycolytic regulator PFKFB3 impairs angiogenesis
- PFKFB3-driven glycolysis overrules the pro-stalk activity of Notch
- PFKFB3 regulates tip and stalk cell behavior, formation of filopodia/lamellipodia and directional migration
Inhibiting glycolysis may enhance the anti-tumor immune response
Inhibition of glycolysis may induce tumor-specific T-cell activation and significantly increase efficacy of conventional chemotherapy PNAS 2012 Dec 4; 109(49):20071-6
“Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response”
- 2DG (2-Deoxy-D-glucose), is a broad inhibitor of glycolysis
- Rapidly dividing immune cells are glycolytic, but 2DG has only a minor adverse effect in mice (even at high concentrations of 2g/kg)
- 2DG + etoposide significantly increases survival of immunocompetent mice, seemingly driven by an enhanced tumor-specific T-cell immune response
Biomarker
JAK2V617F increases expression of Glut1 and PFKFB3 in HEL, BxPC3.
JAK2V617F-transformed HEL cell xenograft tumor growth inhibited by PFKFB3 shRNA. Scr -scrambled shRNA;C, D - PFKFB3-targeting shRNA constructs.
Reddy M. et al., The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity. Leukemia. 2012, 26(3):481-9.
PFKFB3 projectdata
Clinical Biomarker Hypothesis
Genomic markers of drug sensitivity to PFKFB3 inhibitors (mutated genes):-- PIC3CA-- MAP3K-- other…
We are carrying out screening of PFKFB3 inhibitors in cancer cell panel to confirm the identified genomic markers of drug sensitivity.
Genomic markers of drug sensitivity to PFKFB3 inhibitors were identified using bioinformatics methodology described in Garnett et al., Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012; 483(7391): 570–575.
Series of molecules with range of inhibitory activities
Designed PFK2 kinase inhibitors achieve high selectivity and do not bind ATP pocket, thereby reducing off-target toxicity
Molecular simulation and X-ray data confirm molecules bind the fructose, not ATP, pocket
Potent molecules with clear therapeutic window
Potent biological activityPFKFB3 enzymatic assay, EC50
~10nM
Cellular efficacy, EC50
Decrease of intracellular F26BP in a dose-dependent mannerEC50 ~100nM–50uM depending on cell line
Good PK (mouse)
t1/2 (mice) 4 h
Chronic tox (100mg/kg dose, daily for 4 weeks)
No effect on body weight no toxicity markers in histology and blood biochemistry
Dosage form I.P.
Clear efficacy
Pancreatic, liver and colon cancer xenograft (mice)
Growth inhibition at 20 mg/kg, daily
Day 0: Tumor inoculation. Day 14: Beginning of the drug treatment (i.p. administration)сf:- slide-12 (PFKFB3 shRNA); - Gross MI et al., Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer. Mol Cancer Ther. 2014, 13(4)
- Synergy with Irinotecan (CPT-
11)
- No changes in body weight
Preclinical efficacy in colon cancer xenografts HCT-116
Clinical Biomarker Hypothesiscorrelates with in vivo data
Suggested genomic biomarker of drug sensitivity to PFKFB3 inhibition correlates with inhibition of tumor growth in xenograft models in vivo.
Maximal effect in vivo was observed in HCT116 xenograft which is characterized by multiple PFKFB3 overexpression genomic markers.
Genomic markers of drug
SENSITIVITY(high PFKFB3)
Genomic markers of drug
RESISTANCE(low PFKFB3)
Cell line genetic mutations:
Cell line genetic mutations:
Metabolite levelin tumor samplein vivo
• Lactate and TBARS (thiobarbituric acid reactive substances – a measure of lipid peroxidation state) were measured in tumor samples from HT-29 xenograft in mice.
• Consistently with suggested MoA the administration of PFKFB3 inhibitor decreased the levels of lactate and TBARS.
• NAD/NADH and GSH/GSSG level measurement is in progress
(50 mg/kg daily) (50 mg/kg daily)
30 day, non-GLP toxicology study completed
100 mg/kg daily for 30 days:
- No effects on body weight
- No decrease of RBC levels
- No change in liver damage markers
- No pathologic changes in heart, lungs, spleen, liver, kidneys, adrenal glands or stomach
Clinical strategy
TPP
IndicationGlycolytic, aggressive solid tumors initially, followed by others including hematologic cancers, colon cancer, pancreatic, TNBC, HCC
Dosage formIV and PO
Therapeutic end-points
Superior overall survival and improved quality of life versus current standard of care.
Tumor imaging/biomarker
PET scan for tumor glucose uptake, PFKFB3+ biomarker assay development (planned)
SafetyAppears well tolerated with large therapeutic window, enabling combination with other agents
Combination strategies
Clear potential for combining with other agents given safety profile and MoA(e.g. cytotoxics, pro-apoptotic agents, anti-angiogenic, anti-IDH2, glutaminase inhibitors etc.)
Competitive/Reference project:
Advanced Cancer Therapeutics (ACT)
Advanced Cancer Therapeutics is developing PFKFB3 inhibitors of different chemical class.
Compound PFK158 is reported in MedTrack and in patent (http://www.google.com/patents/WO2013148228A1?cl=en) The compound inhibits PFKFB3 in enzymatic assay, decreases glucose uptake and fructose-2,6-bisphosphate level in cell culture, inhibits tumor growth in mouse xenografts in vivo.
In scientific literature compound 3PO (the analogue of PFK158) was reported to:
- Inhibit cancer cell proliferation in vitro (Clem et al., 2008)- inhibit angiogenesis (de Bock et al., 2013)- inhibit proliferation of activated T-cell (Telang et al., 2012)
Competitive/Reference project:
Industry/Academia collaboration example
Kancera is developing PFKFB3 inhibitors of different chemical class.
The in vitro profile is similar to Quantum compounds. Kancera compounds inhibit PFKFB3 in enzymatic assay, decrease fructose-2,6-bisphosphate level in cell culture (patent http://www.google.com/patents/US20130172339), but no data on inhibition of cell proliferation reported.
In recent interim report (http://mb.cision.com/Main/1190/9631826/277472.pdf) Kancera provided results of collaboration with academic research lab:
- Evaluated synergistic effects of PFKFB3 inhibitors with known classes of anticancer drugs
- Next step is to test whether PFKFB3 inhibitors can improve the treatment of advanced lung cancer and metastatic breast cancer
Next steps:Further development up to accomplishing 1b phase clinical trials
•More xenograft/ induced-cancer models models (more cell lines, combinations with known drugs)
•Preclinical candidates selected
•IND enabling studies
•Clinical trials material manufacturing
•IND filing
Partnering opportunities
Looking for clinical co-development, early licensing options
