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Principal Investigator: Goutham Narla
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $503,559
Funding agency: National Cancer Institute
Project Summary / Abstract
Neuroendocrine tumors (NETs) are incurable, clinically challenging malignancies that are rising in incidence.
Although tumors grow slowly, they progress relentlessly and lack effective therapies once they become
metastatic. Many patients with advanced NETs will die from their disease. Greater understanding of
mechanisms driving NET progression and metastasis is needed to inform new therapies and improve patient
outcomes.
We discovered a RABL6A-PP2A pathway that promotes pancreatic NET (PNET) pathogenesis. RABL6A
(RAB-like GTPase) is upregulated in patient PNETs and is required for PNET proliferation and survival.
RABL6A acts through multiple mechanisms that are only partly defined, including inhibition of tumor
suppressors (p27, RB1) and activation of oncogenic pathways (MYC, AKT-mTOR). A common regulator of all
those factors is protein phosphatase 2A (PP2A), a powerful tumor suppressor whose role in NETs has not
been explored. We found that RABL6A activates AKT-mTOR signaling in PNETs by inhibiting PP2A. In turn,
RABL6A is down regulated by PP2A although the molecular mechanism by which these two proteins inhibit
each other's function is unknown. Excitingly, specific `small molecule activators of PP2A' (called SMAPs)
suppress PNET cell proliferation and survival in a RABL6A-dependent manner and abolish tumor growth in
vivo. These findings support a novel strategy for PNET therapy involving PP2A reactivation. However, the role
of RABL6A and PP2A in NET progression is only partly understood and their importance in NET metastasis is
not known. This multi-PI study draws upon the collective knowledge of both PIs and their unique expertise /
resources in NETs (Quelle) and PP2A (Narla) to test the central hypothesis that the RABL6A-PP2A
pathway is a critical driver of NET progression and response to targeted therapies. Aim 1 will determine
the mechanisms of RABL6A-PP2A reciprocal regulation. Aim 2 will define the roles and interdependence of
RABL6A and PP2A in NET progression and metastasis. Aim 3 will establish the importance of the RABL6A-
PP2A alterations in NET pathogenesis and the efficacy of pathway targeted combination therapies.
This project will provide new insights into molecular events driving NET progression and metastasis while
establishing the efficacy of promising NET therapeutics, thus addressing a critical gap in NET research that
may ultimately improve patient outcomes. Moreover, this work builds upon an emerging strategy for anticancer
therapy (i.e., pharmacological reactivation of PP2A), and may have broad cancer relevance beyond NETs
given the importance of RABL6A overexpression and PP2A inactivation in other tumor types.
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