Molecular Pathways: Targeting RAC-p21-Activated Serine-Threonine Kinase Signaling in RAS-Driven Cancers

Cancers driven by oncogenic Ras proteins encompass some of the most deadly human cancer types, and there is a pressing need to develop therapies for these diseases. While recent studies suggest that mutant Ras proteins may yet be druggable, the most promising and advanced efforts involve inhibitors of Ras effector signaling. Most efforts to target Ras signaling have been aimed at the ERK mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling networks. However, to date, no inhibitors of these Ras effector pathways have been effective against RAS mutant cancers. This ineffectiveness is due, in part, to the involvement of additional effectors in Ras-dependent cancer growth, such as the Rac small GTPase and the p21-activated serine-threonine kinases (PAK). PAK proteins are involved in many survival, cell motility, and proliferative pathways in the cell and may present a viable new target in Ras-driven cancers. In this review, we address the role and therapeutic potential of Rac and Group I PAK proteins in driving mutant Ras cancers

Interplanetary CubeSats: Opening the Solar System to a Broad Community at Lower Cost

Interplanetary CubeSats could enable small, low-cost missions beyond low Earth orbit. This class is defined by mass < ~ 10 kg, cost < $30 M, and durations up to 5 years. Over the coming decade, a stretch of each of six distinct technology areas, creating one overarching architecture, could enable comparatively low-cost Solar System exploration missions with capabilities far beyond those demonstrated in small satellites to date. The six technology areas are: (1) CubeSat electronics and subsystems extended to operate in the interplanetary environment, especially radiation and duration of operation; (2) Optical telecommunications to enable very small, low-power uplink/downlink over interplanetary distances; (3) Solar sail propulsion to enable high !V maneuvering using no propellant; (4) Navigation of the Interplanetary Superhighway to enable multiple destinations over reasonable mission durations using achievable !V; (5) Small, highly capable instrumentation enabling acquisition of high-quality scientific and exploration information; and (6) Onboard storage and processing of raw instrument data and navigation information to enable maximum utility of uplink and downlink telecom capacity, and minimal operations staffing. The NASA Innovative Advanced Concepts (NIAC) program in 2011 selected Interplanetary CubeSats for further investigation, some results of which are reported here for Phase 1

Optimizing Spacecraft Placement for Liaison Constellations

A navigation and communications network is proposed to support an anticipated need for infrastructure in the Earth-Moon system. Periodic orbits will host the constellations while a novel, autonomous navigation strategy will guide the spacecraft along their path strictly based on satellite-to-satellite telemetry. In particular, this paper investigates the second stage of a larger constellation optimization scheme for multi-spacecraft systems. That is, following an initial orbit down-selection process, this analysis provides insights into the ancillary problem of spacecraft placement. Two case studies are presented that consider configurations of up to four spacecraft for a halo orbit and a cycler trajectory

Dynamic Optimization of Multi-Spacecraft Relative Navigation Configurations in the Earth-Moon System

In this paper, the notion of relative navigation introduced by Hill, Lo and Born is analyzed for a large class of periodic orbits in the Earth-Moon three-body problem, due to its potential in supporting Moon exploration efforts. In particular, a navigation metric is introduced and used as a cost function to optimize over a class of periodic orbits. While the problem could be solve locally as an optimal control problem, a dynamical based approach that allows for a global/systematic view of the problem is proposed. First, the simpler problem of multiple spacecraft placement on a given periodic orbit is solved before the notion of continuation and bifurcation analysis is used to expand the range of solutions thus obtained

Molecular Pathways: Targeting RAC–p21-Activated Serine–Threonine Kinase Signaling in RAS-Driven Cancers

Cancers driven by oncogenic Ras proteins encompass some of the most deadly human cancer types, and there is a pressing need to develop therapies for these diseases. While recent studies suggest that mutant Ras proteins may yet be druggable, the most promising and advanced efforts involve inhibitors of Ras effector signaling. Most efforts to target Ras signaling have been aimed at the ERK mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling networks. However, to date, no inhibitors of these Ras effector pathways have been effective against RAS mutant cancers. This ineffectiveness is due, in part, to the involvement of additional effectors in Ras-dependent cancer growth, such as the Rac small GTPase and the p21-activated serine-threonine kinases (PAK). PAK proteins are involved in many survival, cell motility, and proliferative pathways in the cell and may present a viable new target in Ras-driven cancers. In this review, we address the role and therapeutic potential of Rac and Group I PAK proteins in driving mutant Ras cancers

Interplanetary Cubesat Architecture and Missions

No abstract availabl

Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

There is now considerable and increasing evidence for a causal role of aberrant activity of the Ras superfamily of small GTPases in human cancers. These GTPases act as GDP-GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. We assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics