Leptomeningeal metastases in medulloblastoma (MB), the most common solid malignant pediatric cancer, strongly predicts poor prognosis. Leptomeningeal metastases at diagnosis are found in 40% of patients with particularly aggressive subgroups of MB. Furthermore, over 80% of patients have leptomeningeal metastases at recurrence and most die within one year. There is a gap in understanding the molecular underpinnings and treatment of leptomeningeal MB metastases. The Abelson (ABL) family kinases play an important role in lung cancer cell migration, invasion, cell adhesion, and chemotherapy resistance. We have recently found significantly elevated ABL1 and ABL2 expression in children with MB subgroups most likely to disseminate and in MB patients with metastases at diagnosis. ABL kinases likely mediate leptomeningeal metastases via two mechanisms, 1) cell proliferation via c-myc activation and 2) cell binding/migration via integrin/cadherin activation. First, ABL1 is a key regulator in the expression of the oncogene, c-myc, in fibroblasts. C-myc is overexpressed MB subgroups most likely to metastasize throughout the leptomeningeal compartment. Second, ?1 integrin and E-cadherin engagement by extracellular matrix (ECM) proteins activate ABL kinases to produce focal adhesions in fibroblasts. We have previously identified integrins as key mediators in MB migration and adhesion. Our overall objectives in this application are to 1) elucidate the relationship between ABL1/2 and c-myc expression in MB in vitro, 2) elucidate the relationship between ABL1/2 and integrin/E-cadherin complex formation in MB in vitro, and 3) determine the importance of ABL1/2 expression and pharmacologic inhibition in vivo. These results will provide the scientific foundation for future 1) detailed explorations into the signaling pathways of ABL1/2 in medulloblastoma, 2) in vivo testing of ABL kinase inhibitors for other pediatric brain tumors, 3) in vivo combination chemotherapy, and ultimately, 4) clinical trials. Our central hypothesis is that knocking down and pharmacologically inhibiting ABL1 and 2 will decrease c-myc expression and integrin/E- cadherin complex formation thereby resulting in decreased cell proliferation, binding, and migration in the leptomeningeal compartment. To attain the overall objectives, the following specific aim and sub-aims will be pursued.
Aim 1 : Unravel the role of ABL 1 and 2 as drivers of medulloblastoma leptomeningeal metastases.
Sub Aim 1 a: Determine the effect of ABL 1/2 knockdown and pharmacologic inhibition on c-myc expression and cellular proliferation.
Sub Aim 1 b: Determine the effect of ABL1/2 knockdown and pharmacologic inhibition on ?1 integrin/E-cadherin expression and cellular dissemination.
Sub Aim 1 c: Determine the effect of ABL1/2 genetic inactivation on leptomeningeal tumor formation in vivo.
Sub Aim 1 d: Determine the effect of pharmacological ABL 1/2 inhibition for the treatment of leptomeningeal metastases in vivo.
Medulloblastoma is the most common malignant pediatric brain tumor and leptomeningeal metastases of medulloblastoma portend a dismal prognosis. This project focuses on elucidating the role of ABL kinases as drivers of medulloblastoma cell proliferation, migration, and adhesion in the leptomeningeal compartment. Inhibition of ABL kinases has the potential to improve survival and the quality of life of children with medulloblastoma leptomeningeal metastases.