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 of the PI3K after chemo- therapy

I 3 classes II III Chemical  Are the most studied Biological structure function  Involved in regulation of  Cell cycle  Apoptosis  Cell metabolism  Angiogenesis Small molecule In Leukemia  Motility inhibitors PI3K  Structure Drug resistance In Drug resistance Regulatory Catalytic subunit subunit

Chemical Biological structure function Small molecule Genetic PI3K alteration inhibitors Drug Drug resistance resistance In hematologic malignancies

PI3K inhibitors Isoform-specific inhibitors Pan-PI3K inhibitors CAL-101 NVP-BKM  Oral, p110 δ inhibitor  Oral, p110 α / β / δ inhibitor  acceptable safety and tolerability profile  acceptable safety and tolerability profile  progressed into phase III clinical trials  progressed into clinical trials

 Jurkat  KG-1 RPMI KMM1  HL-60 Mutant 8226 Mutant  U937 p53 p53 REH Nalm-6 Multiple Wild-type Mutant Mutant Wild-type Myeloma PTEN PTEN p53 p53 cell lines Pre-B ALL Mutant Wild-type cell lines Cell Other MOLT-4 PTEN PTEN cell lines Wild-type lines p53 T- ALL Mutant cell line NB4 APL Mutant PTEN cell line p53 Wild-type PTEN

1 Effects on NVP-BKM dosage for PI3K/Akt pathway CAL-101 dosage for PI3K abrogation is PI3K abrogation is 2 µM . 20 µM . NVP-BKM completely CAL-101 partially inhibited Akt inhibited Akt phosphorylation phosphorylation

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

2 Anti-proliferative Cytotoxic effects effects

2 Apoptotic Cytotoxic effects effects FL1-Annexin FL1-Annexin FL1-Annexin FL1-Annexin FL3-PI FL3-PI

PI PI3K sig ignaling & ROS production Production of intercellular ROS is one of 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 ROS Apoptotic production effects

Exerted both cytotoxic and anti-proliferative effect. Reduced the survival rate of hematologic malignant cells irrespective of the prognostic markers. irrespective of the prognostic markers. p53 PTEN Trigger ROS-dependent apoptotic cell death in all cell lines.

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 of NF- κB .

3 NF- κ B pathway

CAL-101 NVP-BKM

Re Resea search Hi rch Highligh ghlights ts

 Both PI3K inhibitors induced apoptosis in all tested cell lines, indicating the potential application of the inhibitors in either wild-type or deficient p53/PTEN-  Abrogation of PI3K/Akt signaling pathway reduced expressing leukemic cells. the survival and proliferative capacity of hematologic malignant cells.  NVP-BKM is a more potent inhibitor than CAL-101,  Complete inhibition of class I PI3K activity which not only inhibited PI3K/Akt signaling more effectively abrogated leukemic cell pathway but also suppressed NF- κ B signaling. proliferation and survival.

Thank you for your attention