AT-101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenström macroglobulinaemia.

[waldenström macroglobulinemia]

Multiple myeloma , the second most common haematological malignancy in the U .S ., is currently incurable . Disruption of the intrinsic apoptotic pathway by BCL 2 and MCL 1 upregulation is observed in >80 % of myeloma cases and is associated with an aggressive clinical course . Remarkably , there is no approved drug with the ability to target BCL 2 or MCL 1 . Thus , we investigated the anti-tumour effects of a pan-BCL 2 inhibitor , AT-101 , which has high binding specificity for BCL 2 and MCL 1 in preclinical models of plasma cell cancers (Multiple myeloma and Waldenström macroglobulinaemia ). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL 2 family members . AT-101 was able to downregulate BCL 2 and MCL 1 in all plasma cell cancer models and induced apoptotic cell death in a caspase-dependent manner by altering mitochondrial membrane permeability . This cytotoxic effect and BCL 2 downregulation were further potentiated when AT-101 was combined with lenalidomide /dexamethasone (LDA ). NanoString nCounter mRNA quantification and Ingenuity Pathways Analysis revealed differential changes in the CCNA 2 , FRZB , FYN , IRF 1 , PTPN 11 genes in LDA -treated cells . In summary , we describe for the first time the cellular and molecular events associated with the use of AT-101 in combination with lenalidomide /dexamethasone in preclinical models of plasma cell malignancy .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated