Cancer continues to be a leading cause of death worldwide. Despite significant efforts devoted towards
developing effective treatments, the survival rates remain low in many types of tumors. The long-term goal of
both the F99 and K00 phases of this work will be to reveal new strategies that lead to novel anti-cancer therapies.
The F99 phase will be focused on a cell-intrinsic aspect of cancer biology, while the K00 phase will focus on an
immune cell with great potential to directly inhibit tumor growth and to modulate the efficacy of already approved
The F99 phase: An increasing body of evidence has shown that many cancer cells develop an addiction
to the nuclear transport machinery and have increased numbers of Nuclear Pore Complexes (NPCs), the multi-
protein structures that regulate the nucleocytoplasmic transport of molecules. Recent work has revealed that
inhibition of the assembly of NPCs could represent an effective target for cancer therapeutics. However, the
molecular factors that regulate NPC assembly are incompletely understood and a targetable pathway has yet to
be identified. A whole genome siRNA screen was performed to find genes that regulate assembly of these
structures. Genes were identified that, when knocked down, either increase or decrease the NPC content on the
surface of the nucleus. Knockdown of 3 members of the CCR4-NOT complex were found to increase NPCs. The
CCR4-NOT is a major deadenylase complex that controls protein levels via regulation of mRNA metabolism in
eukaryotes. The work proposed here will characterize the effect of CNOT knockdown on the NPC
number/functionality and how these changes alter basic cellular physiology. Additionally, this work will elucidate
the molecular mechanism by which the CCR4-NOT complex regulates NPCs.
The K00 phase: In recent years immuno-oncology therapies, namely immune checkpoint blockers, have
shown remarkable clinical efficacy however only a small proportion of patients respond to treatments. One of the
reasons underlying the lack of efficacy stems from the presence of a strong immunosuppressive tumor
microenvironment (TME). Until the TME can be modified into a more immuno-activating environment, immune
checkpoint blockade therapies will have limited success. The K00 phase of this project will focus on a unique
and dynamic leukocyte that strongly contributes to the observed immunosuppression; the Tumor-Associated
Macrophage (TAM). TAMs have been shown to compose up to 50% of a tumor’s mass and have both pro- and
anti-tumorigenic phenotypes. The need remains to develop more effective strategies to target this cell type and
reprogram it. The K00 research will characterize the transcriptional networks that can be harnessed to modulate
macrophage repolarization in the TME.
Successful completion of the F99 phase will reveal a targetable cell-intrinsic aspect of cancer
biology, while completion of the K00 phase will reveal an immuno-oncology targetable pathway.