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ICGEB Council of Scientific Advisers – Twenty-second session – Trieste, Italy, 17-18 May 2016

1

GENERAL PROGRAMME

Tuesday, 17 May 2016 09.00 - 10.30: CSA session: Plenary meeting

10.30 - 11.00: Coffee Break – ICGEB Atrium (CSA Members)

11.00 - 13.00: CSA session: Plenary meeting (cont.) 13.00 -14.00: Lunch Break – ICGEB Common Room (CSA Members)

14.00 -15.40: Scientific Presentations by ICGEB Research Groups (20+5’ per Group)

• Bacteriology • Biotechnology Development Unit

• Biosafety

• Human Molecular Genetics 15.40 - 16.00: Coffee Break – ICGEB Atrium

16.00 - 17.40: Scientific Presentations (continued)

• Cardiovascular Biology • Molecular Medicine

• Molecular Cardiology

• Molecular Hematology

17.45: Transportation to Hotels (Shuttle bus)

MOLECULAR HEMATOLOGY GROUP

Dimitar Efremov Dimitar.efremov@icgeb.org

ICGEB Cluster Smart Health FVG

Trieste 20 May 2016

Primary disease target: Chronic Lymphocytic Leukemia (CLL)

Objectives:

Molecular Hematology Group: Main Research Interests

Most common adult leukemia in western countries - accounts for 40% of all leukemia diagnosis - median age at diagnosis ~70 years

B cell malignancies: - leukemia, lymphoma, multiple myeloma

Incurable with standard chemotherapy

Understand cellular and molecular mechanisms that drive B cell malignancies Develop novel approaches for targeted therapy of B cell malignancies

Chronic lymphocytic leukemia: pathogenesis

Genetic defects:

Microenvironmental signals: - Antigen / B-cell receptor (BCR) - CpG-DNA / TLR9 - CD40L / CD40 - VCAM-1 / VLA-4 - BAFF / BAFF-R - CXCL12 / CXCR4

Stromal cell

CLL cell

T cell

Monocytes

Follicular dendritic

cell

CD40L CD40

Antigen BCR VLA-4 VCAM-1

CXCL12

CXCR4 BAFF-R

BAFF CD38 CD31

Identification of therapeutic targets along the B cell receptor (BCR) pathway in CLL cells

IgM

P P

P P

LYN

CD19

SYK SYK

BLNK

BCAP PI3Kδ

PI3KδPIP3

AKT BTK

GSK3

FOXO

mTORC1

BTK

NFAT

PLCγ2

IP3 DAG

Ca2+

NF-κB

PKC

PIP2

Fostamatinib

Gobessi S et al, Leukemia 2009; 23:686 Suljagic M et al, Blood 2010; 116:4894-905

Mechanism of action of Fostamatinib: Modestly cytotoxic for CLL cell in vitro

Inhibits leukemia proliferation and induces leukemia regression in Eµ-TCL1 transgenic murine model of CLL in vivo

Petlickovski A et al, Blood 2005; 105:4820-7 Gobessi S et al, Blood 2007; 109:2032-9 Longo P et al, Blood 2008; 111:846-55 Woyach J et al, Blood. 2014; 123:1207-13

B cell receptor inhibitors

High response rates

Prolonged responses

Minimal toxicity

Few complete responses

High costs of treatment

Resistance with prolonged therapy

Oral drugs

Common features of BCR inhibitors Target Drug Disease Stage of development

SYK Fostamatinib CLL, NHL RA, AIHA, ITP

Phase 2 Phase 3

SYK Entospletinib CLL, NHL Phase 2

SYK/JAK Cerdulatinib CLL, NHL Phase 1/2

BTK Ibrutinib CLL, MCL, WM Approved

BTK Acalabrutinib CLL, NHL Phase 2

BTK CC-292 CLL, NHL Phase 1

PI3Kδ Idelalisib CLL, SLL, FL Approved

PI3Kδ/γ Duvelisib CLL, NHL Phase 2

pan-PI3K Pilaralisib CLL, NHL Phase 1

Ongoing and future studies

Novel drugs: - drugs that target microenvironmental signals (IRAK4 inhibitors) - drugs that directly kill CLL cells (novel BCL-2 inhibitors)

Combination treatments: - combinations of BCR signaling inhibitors with BCL-2 inhibitors

Mechanisms of resistance to novel targeted therapies: - tests to predict response to treatment