1. A multi-pronged approach to Immuno-Oncology

2. Immuno-oncology has revolutionized cancer treatment
How can it be improved further?
Immunotherapy + ?
Combine Immune-activation with
Reducing metastases
Reducing relapses
Synergy with chemotherapy
immunotherapy

3. Aryl hydrocarbon Receptor (AhR)
Ligand-activated transcription factor
Strongly up-regulated in many cancers
Constantly activated in tumor
Expression of cancer-related genes
Constant activation by
agonist ligands
Including:
Tryptophan metabolites
Immune suppression
IDO/TDO expression
Induction of Tregs
Anti-inflammation
Pro-metastatic
Cancer Stem Cell induction
Anti-apoptotic
Oncogene activation
Angiogenesis
the environmental ligand's that activate the AHR have already been linked to increased breast cancer incidence. Now we have an idea about the mechanism how. Those chemicals would include dioxins, PCBs, and polycyclic aromatic hydrocarbons.
in normal cells there are extremely low levels of AHR in the cytoplasm. Once activated by environmental ligand's it becomes an active transcription factor translocate to the nucleus and regulating transcription of probably a dozen or more genes. CYP1A1 and CYP1B1 are classic AHR responsive genes. In the cancer cells, the transcription factor is expressed at huge levels, sometimes 50 times more than in any normal cell, and it is constructively active. we now have strong evidence that the tumors produce amino acid metabolites that activate the AHR. These are the endogenous ligands. Excessive production of these metabolites has previously been associated with breast cancer. Now we know why. They constantly activate AhR.

4. Blocking by antagonist ligand
CB AhR inhibitor
CB binding prevents:
AhR from entering the nucleus
Cancer-related gene transcription
Hercules has developed CB , a small molecule AhR inhibitor CB CB
Effects
Immune activation
IDO/TDO inhibition
Reduction of Tregs
Reduction of Treg IL-10
Pro-inflammation
Anti-metastatic
Cancer stem cell inhibition
Cancer cell apoptosis
Anti-Angiogenic CB
Blocking by antagonist ligand CB
the environmental ligand's that activate the AHR have already been linked to increased breast cancer incidence. Now we have an idea about the mechanism how. Those chemicals would include dioxins, PCBs, and polycyclic aromatic hydrocarbons.
in normal cells there are extremely low levels of AHR in the cytoplasm. Once activated by environmental ligand's it becomes an active transcription factor translocate to the nucleus and regulating transcription of probably a dozen or more genes. CYP1A1 and CYP1B1 are classic AHR responsive genes. In the cancer cells, the transcription factor is expressed at huge levels, sometimes 50 times more than in any normal cell, and it is constructively active. we now have strong evidence that the tumors produce amino acid metabolites that activate the AHR. These are the endogenous ligands. Excessive production of these metabolites has previously been associated with breast cancer. Now we know why. They constantly activate AhR. CB

5. CB7993113 Improves Survival in Immunodeficient Murine Cancer Model
50 mg/kg/day oral.
n=12 mice per group
Human oral squamous carcinoma cell line, Cal27, in an orthotopic xenograft (tongue)
90% survival
AhR blocking is also effective in models without active immune system
25% survival

6. CB7993113 Blocks Human Breast Cancer Metastasis in a Zebrafish Model
24 Hours after injection of human RFP-MDA-MB-231 TNBC cells
Metastasis/Fish
0.1% DMSO (Control) n=12
1 uM CB n=6
Treated for how long? 24 hours
These results in zebrafish show metastasis blocking effect and are also indicative of lack of toxicity of CB

7. CB7993113 reduces tumor burden in immunodeficient murine TNBC model
Total Tumor Burden After Intracardiac Injection of MDA-MB-231-BO
Bioluminescence
Daily injection of 25mg/kg ip CB
MDA-MB-231BO human TNBC tumor cells

8. CB7993113 Clinical Development
Correlation between cancer aggression and AhR expression
Focus on aggressive cancers
TNBC
Glioblastoma
Contrary to most immuno-oncology approaches, CB may be effective in colorectal cancers
CB could be combined with:
Check-point inhibitors
Cancer vaccines
Chemotherapy
Target Profile:
Oral, non toxic, chronic treatment of epithelial cancers

9. Hercules Team Based in Amsterdam, Netherlands, since 2013
Spin off from Boston University
Bart Wuurman
CEO
Previously: CEO Lanthio Pharma, AM-Pharma
Prof David Sherr
CSO
Scientific founder, based in Boston
Sjoerd Wadman
Development Director
Previously Lanthio Pharma, GSK

10. Finance Shareholding: DDF Ventures; 60% shareholder Current funding:
Eurostars Grant funding for
additional in-vivo efficacy studies
pre-clinical development of CB
Funding need: €10m
Build team
Phase I and IIa

11. Summary AhR inhibition with CB7993113: Anti-tumor immune activation
Reduced metastatic behaviour
Reduced potential for relaps
Increased efficacy for chemotherapy
Clinical focus on aggressive tumors

12. Thank you for your attention