This oral presentation made at ESOC Marbella 2016 by Eric Raymond describes the role of bromodomain proteins in transcription and updates data on drugs inhibiting bromodomain functions in cancer cells. Data on NUT moline carcinoma, lymphoma, leukemia, prostate, breast, lung carcinomas and neuroblastoma are recapitulated using JQ1 and 0TX-015.

1. Bromodomain inhibitors
Eric Raymond MD, PhD
Chair of Medical Oncology
@ Groupe Hospitalier Paris Saint-Joseph - France
eraymond@hpsj.fr

2. Disclosures
– Oncoethyx
– Pfizer
– Novartis
– Eli Lilly
– Ipsen

3. Cancer May Arise from Aberrant
Epigenetic Chromatin Regulation
Nature Reviews Molecular Cell Biology 16, 258–264 (2015)
Histone acetyltransferases (HATs)
and methyltransferases
Histone deacetylases
(HDAC) and demethylases
Bromodomain containing proteins
key oncogenes and
anti-apoptotic
proteins

4. Bromodomain Proteins Are Unpacking DNA & Help Activating RNA
Polymerase for Initiation of Gene Transcription
Nature Reviews Molecular Cell Biology 16, 258–264 (2015)
Nuclear Protein in Testis
NUT midline carcinoma (NMC) is characterized by a single
t(15;19)(q14;p13.1) chromosomal translocation
Positive
Transcription
Elongation
Factor B

5. Further to Bromodomain Reader Activation,
Initiation of RNA Synthesis May Proceed

6. Potential of Bromodomain Inhibitors in Cancer Therapy
NUT midline
carcinoma
BRD4–NUT-fusion
Driving oncogene
May depend of the context
MYC-dependent tumors
Lymphoma/leukemia
Hormone resistant prostate
cancer
Triple negative breast cancer
ALK lung carcinoma
Regulation of transcription
Synergy with
many cytotoxic
and targeted
agents
Combinations

7. Conclusions
• Bromodomain family of proteins are involved in
reading of acetylated DNA and facilitate the
initiation of transcription of major oncogenes such
as c-myc
• Bromodomain inhibitors are novel class of
molecules with potential activity in a wild range of
tumor types either alone or in combination
• Phase I trials with bromodomain inhibitors showed
proof of concept activity in BRD-activated tumors
such as NUT midline carcinoma, leukemia, and
lymphoma

8. Predicted Druggability and Binding of
Small Molecules to Bromodomains
BRD complexes
Nat Rev Cancer 12:465-477, 2012

9. Bromodomain Inhibitors in Clinical Trials
Ther Adv Hematol, Vol. 6(3) 128–141, 2015

10. Potential Tumors That Can Be
Sensitive to Bromodomain Inhibitors
• NUT-midline carcinoma
• MYC dependent tumors
– Multiple myeloma
– Non-Hodgkin and Burkitt lymphoma
– Medulloblastoma
• Acute myeloid leukemia
• Hepatocellular carcinoma
• Pancreatic cancer
• Castration-resistant prostate cancer
• Triple negative breast cancer
• ALK-positive non-small cell lung cancer
JQ1 has been a lead for
preclinical experiments but
was not suitable for clinical
development

11. Bromodomain Inhibition Leads to Gene Expression
Changes That May Affect Hematological Malignancies
Ther Adv Hematol, Vol. 6(3) 128–141, 2015

12. OTX-015 Alone and in Combination in
B-cell Lymphoma
Eugenio Gaudio et al. AACR 2014

13. Combinations of OTX-015 in Leukemia Cells
Lucile Astorgues-Xerri et al. AACR 2014

14. OTX015 in Non-Small-Cell Lung Cancer Cells Bearing the
Fusion Protein EML4–ALK
c-myc n-myc
Ramiro Vazquez et al. AACR 2014

15. OTX-015 in Neuroblastoma Models
Johannes H. Schulte et al., AACR 2014

16. First-in-Human Phase I Data of OTX-015
• Humans with lymphoma or acute leukemia given up to 60 mg/day
oral OTX015 experienced thrombocytopenia as a dose-limiting
toxicity
• Nausea and fatigue were also observed
• NUT-midline carcinoma (3 patients):
– Rapid tumor regression and symptomatic improvement (18 & 19
months) in two patients
– A third patient stabilized and demonstrated metabolic response
• Hematological malignancies (28 patients):
– Two patients with acute myelogenous leukemia (AML) demonstrated a
complete response
– Two patients with lymphoma had a partial response
• Hormone refractory prostate cancer
– Several patients demonstrated significant PSA decreases
Advances in Cancer Research, 131, 2016, Pages 21–58

17. Pharmacokinetic Data of Oral OTX-015 in
Patients With Hematological Malignancies
Elodie Odore et al. AACR 2014

18. OTX-015 in NUT Midline Carcinoma
Clinical proof of concept
NMC are defined by rearrangements of the
NUT, aka NUTM1, gene on chromosome
15.q14
Most commonly the rearrangement is a
translocation between BRD4 (chr. 19p13.1)
and NUT, forming the BRD4–NUT-fusion in
75–80% of cases
NMC is one of the most aggressive solid
tumor known, having a
median survival of 6.7 months
Baseline OTX-015
Advances in Cancer Research, 131, 2016, Pages 21–58
NUT stands for Nuclear Protein in Testis

19. Resistance to Bromodomain Inhibitors
• Activation of the Wnt/β-catenin pathway in
leukemia cells
– The resistance to BET inhibition occurred despite
continued inhibition of BRD4 targets
– BRD4-dependence is bypassed and Wnt/β-cat
overtakes to activate MYC
• Constitutive phosphorylation of BRD4 in triple
negative breast cancer cells
• NMC?
Advances in Cancer Research, 131, 2016, Pages 21–58

20. Potential of Bromodomain Inhibitors in Cancer Therapy
NUT midline
carcinoma
BRD4–NUT-fusion
Driving oncogene
May depend of the context
MYC-dependent tumors
Lymphoma/leukemia
Hormone resistant prostate
cancer
Triple negative breast cancer
ALK lung carcinoma
Regulation of transcription
Synergy with
many cytotoxic
and targeted
agents
Combinations

21. Conclusions
• Bromodomain family of proteins are involved in
reading of acetylated DNA and facilitate the
initiation of transcription of major oncogenes such
as c-myc
• Bromodomain inhibitors are novel class of
molecules with potential activity in a wild range of
tumor types either alone or in combination
• Phase I trials with bromodomain inhibitors showed
proof of concept activity in BRD-activated tumors
such as NUT midline carcinoma, leukemia, and
lymphoma

22. Thanks for your attention
Eric Raymond MD, PhD
Chair of Medical Oncology
@ Groupe Hospitalier Paris Saint-Joseph
France
eraymond@hpsj.fr