malignancy treatment Therapeutic application of PI3K inhibitors - - PowerPoint PPT Presentation

New opportunities in Hematologic malignancy treatment

Therapeutic application of PI3K inhibitors

Second cause of death, worldwide Despite improvement in the therapeutic approaches, still a proportion of patients loss their lives.

In 1990, Nicholas Lyndon

Trastuzumab

• Breast cancer
• Targeting HER2

Erlotinib & Gefitinib

• Lung cancer
• Targeting EGFR

The success of Targeted therapy in Hematologic malignancies is more prominent than solid tumors

PIK3CA is mostly mutated in different hematologic malignancies PI3K could be involved in the initiation of leukemia development Other alteration instead of PIK3CA mutation in the component of PI3K pathway in hematologic malignancies.

We studied the mutation of PIK3CA in different hematologic malignant patients at Taleghani and Mofid Hospital AML ALL MM  Highlighted the activation of PI3K axis in hematologic malignancies  The activation

• f the PI3K

after chemo- therapy

Drug resistance

PI3K Biological function Chemical structure

In Leukemia In Drug resistance Small molecule inhibitors

3 classes I II III

 Are the most studied  Involved in regulation of  Cell cycle  Apoptosis  Cell metabolism  Angiogenesis  Motility  Structure

Regulatory subunit Catalytic subunit

Drug resistance

PI3K

Biological function

Chemical structure

Genetic alteration

In hematologic malignancies Small molecule inhibitors

Drug resistance

PI3K inhibitors Isoform-specific inhibitors CAL-101 Pan-PI3K inhibitors NVP-BKM

• Oral, p110 δ inhibitor
• acceptable safety and tolerability profile
• progressed into phase III clinical trials
• Oral, p110 α/β/δ inhibitor
• acceptable safety and tolerability profile
• progressed into clinical trials

APL cell line Other cell lines Multiple Myeloma cell lines Pre-B ALL cell lines T- ALL cell line

Cell lines

Mutant p53 Wild-type PTEN

RPMI 8226

Mutant p53 Mutant PTEN

KMM1 Wild-type p53 Mutant PTEN Nalm-6

Mutant p53

Wild-type PTEN

REH

Wild-type p53 Mutant PTEN MOLT-4 Mutant p53 Wild-type PTEN NB4

 Jurkat  KG-1  HL-60  U937

1 Effects on PI3K/Akt pathway

CAL-101 dosage for PI3K abrogation is 20 µM. CAL-101 partially inhibited Akt phosphorylation NVP-BKM dosage for PI3K abrogation is 2 µM. NVP-BKM completely inhibited Akt phosphorylation

2

NVP-BKM reduced cell survival dose- dependently. IC50 ranged between 1.5-3.5 µM at 24 h. CAL-101 reduced cell survival dose- dependently. IC50 ranged between 15-80 µM at 24 h.

Cytotoxic effects

2 Cytotoxic effects Anti-proliferative effects

2 Cytotoxic effects Apoptotic effects

FL1-Annexin FL3-PI FL1-Annexin FL3-PI FL1-Annexin FL1-Annexin

PI PI3K sig ignaling & ROS production

Production of intercellular ROS is one

• f the main mechanism through which

plenty anti-cancer agents induce cell death in cancer cells. Several mediators such as p73 and FOXO3a are involved in ROS production.

2 Apoptotic effects ROS production

Exerted both cytotoxic and anti-proliferative effect. Reduced the survival rate of hematologic malignant cells irrespective of the prognostic markers. Trigger ROS-dependent apoptotic cell death in all cell lines. irrespective of the prognostic markers.

p53 PTEN

Examination of the other pathways

A well-known molecule involved in drug resistance A side effect of many commonly used chemotherapeutic drugs is the activation

• f NF-κB.

3 NF-κB pathway

CAL-101 NVP-BKM

Re Resea search Hi rch Highligh ghlights ts

 Abrogation of PI3K/Akt signaling pathway reduced the survival and proliferative capacity

• f

hematologic malignant cells.  Both PI3K inhibitors induced apoptosis in all tested cell lines, indicating the potential application

• f

the inhibitors in either wild-type or deficient p53/PTEN- expressing leukemic cells.  NVP-BKM is a more potent inhibitor than CAL-101, which not

• nly

inhibited PI3K/Akt signaling pathway but also suppressed NF-κB signaling.  Complete inhibition of class I PI3K activity more effectively abrogated leukemic cell proliferation and survival.

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