Everolimus HOUGHTON, Peter J
Clinical cancer research,
03/2010, Volume:
16, Issue:
5
Journal Article
Peer reviewed
Open access
Everolimus, an orally administered rapamycin analog, has recently been approved by the U.S. Food and Drug Administration for treatment of renal cell carcinoma (RCC) refractory to inhibitors of ...vascular endothelial growth factor (VEGF) receptor signaling. Everolimus significantly increased progression-free survival (median PFS for the everolimus treated group was 4.0 months versus 1.9 months for the placebo group), although tumor regressions were observed only infrequently. Although the target for everolimus, the serine-threonine kinase mammalian target of rapamycin (mTOR) is well established, the mechanism by which this agent retards tumor growth is not well defined. Further, biomarkers that predict tumor sensitivity are still elusive. The mechanism of action, preclinical antitumor activity, and clinical activity of everolimus against RCC are reviewed.
Rapamycin, a macrocyclic lactone, is a highly specific inhibitor of the serine/threonine protein kinase target of rapamycin (TOR). Although it is clear that TOR controls initiation of protein ...translation, recent results indicate that TOR is a central controller, integrating a plethora of signalling pathways that respond to growth factors and nutritional status. In addition to the role of rapamycin as an immune suppressant, emerging data indicate that genetic and metabolic changes accompanying malignant transformation might cause hypersensitivity to TOR inhibition.
Heterotransplantation of human cancer cells or tumor biopsies into immunodeficient rodents (xenograft models) has, for the past two decades, constituted the major preclinical screen for the ...development of novel cancer therapeutics. Despite limitations, these models have identified clinically efficacious agents, and remain the 'workhorse' of the pharmaceutical industry. However, if therapeutic approaches to treating tumors according to their molecular characteristics are to be achieved, additional new models of human cancer will be required to represent the genetic diversity that exists within tumor histologies. This protocol details a method for establishing xenografts from primary solid-tumor isolates or cells grown in culture. The procedure relies on immunodeficient mice to provide a host for the establishment of human xenografts. The procedure can be completed in 1-2 h with results being obtained in 1-4 months.
Cancers cause significant mortality and morbidity in adolescents and young adults (AYAs), but their biological underpinnings are incompletely understood. Here, we analyze clinical and genomic ...disparities between AYAs and older adults (OAs) in more than 100,000 cancer patients. We find significant differences in clinical presentation between AYAs and OAs, including sex, metastasis rates, race and ethnicity, and cancer histology. In most cancer types, AYA tumors show lower mutation burden and less genome instability. Accordingly, most cancer genes show less mutations and copy number changes in AYAs, including the noncoding TERT promoter mutations. However, CTNNB1 and BRAF mutations are consistently overrepresented in AYAs across multiple cancer types. AYA tumors also exhibit more driver gene fusions that are frequently observed in pediatric cancers. We find that histology is an important contributor to genetic disparities between AYAs and OAs. Mutational signature analysis of hypermutators shows stronger endogenous mutational processes such as MMR-deficiency but weaker exogenous processes such as tobacco exposure in AYAs. Finally, we demonstrate a panoramic view of clinically actionable genetic events in AYA tumors.
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined ...the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.
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•Acute suppression of KRAS causes proteasome-dependent degradation of MYC protein•KRAS regulates MYC protein stability by ERK but not by PI3K-AKT effector signaling•ERK1/2-inhibition-induced feedforward activation of EGFR-MEK5-ERK5 blocks MYC loss•Inhibiting ERK1/2 and ERK5 synergistically causes MYC loss and inhibits PDAC growth
Vaseva et al. find that mutant KRAS regulates MYC via ERK1/2-dependent and -independent mechanisms in pancreatic cancer (PDAC). ERK1/2 blockade activates a compensatory EGFR-SRC-ERK5 cascade that stabilizes MYC, and combined ERK1/2 and ERK5 inhibition promotes synergistic loss of MYC and suppresses PDAC growth.
The mTOR complex-1 (mTORC1) coordinates cell growth and metabolism, acting as a restriction point under stress conditions such as low oxygen tension (hypoxia). Hypoxia suppresses mTORC1 signaling. ...However, the signals by which hypoxia suppresses mTORC1 are only partially understood, and a direct link between hypoxia-driven physiological stress and the regulation of mTORC1 signaling is unknown. Here we show that hypoxia results in ataxia telangiectasia mutated (ATM)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (HIF-1α) on serine696 and mediates downregulation of mTORC1 signaling. Deregulation of these pathways in pediatric solid tumor xenografts suggests a link between mTORC1 dysregulation and solid tumor development and points to an important role for hypoxic regulation of mTORC1 activity in tumor development.
► Negative regulation of mTORC1 signaling by hypoxia is ATM dependent ► ATM-dependent phosphorylation of HIF1α(Ser696) is required for mTORC1 regulation ► Maintained mTORC1 signaling in ATM−/− cells under hypoxia leads to apoptosis ► Childhood solid tumors show 10- to 20-fold lower ATM levels than leukemias
Angiogenesis and metastasis are well recognized as processes fundamental to the development of malignancy. Both processes involve the coordination of multiple cellular and chemical activities through ...myriad signaling networks, providing a mass of potential targets for therapeutic intervention. This review will focus on one master regulator of cell motility, RAC1, and the existing data with regard to its role in cell motility, including particular roles for tumor angiogenesis and invasion/metastasis. We also emphasize the preclinical investigations carried out with RAC1 inhibitors to evaluate the therapeutic potential of this target. Herein, we explore potential future directions as well as the challenges of targeting RAC1 in the treatment of cancer. Recent insights at the molecular and cellular levels are paving the way for a more directed and detailed approach to target mechanisms of RAC1 regulating angiogenesis and metastasis. Understanding these mechanisms may provide insight into RAC1 signaling components as alternative therapeutic targets for tumor angiogenesis and metastasis.
B-cell lymphoma extra large (BCL-X
) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X
inhibitors, such as ABT263, as safe and ...effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-X
proteolysis-targeting chimera (PROTAC), that targets BCL-X
to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-X
-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-X
.
The centromere is essential for ensuring high-fidelity transmission of chromosomes. CENP-A, the centromeric histone H3 variant, is thought to be the epigenetic mark of centromere identity. CENP-A ...deposition at the centromere is crucial for proper centromere function and inheritance. Despite its importance, the precise mechanism responsible for maintenance of centromere position remains obscure. Here, we report a mechanism to maintain centromere identity. We demonstrate that CENP-A interacts with EWSR1 (Ewing sarcoma breakpoint region 1) and EWSR1-FLI1 (the oncogenic fusion protein in Ewing sarcoma). EWSR1 is required for maintaining CENP-A at the centromere in interphase cells. EWSR1 and EWSR1-FLI1 bind CENP-A through the SYGQ2 region within the prion-like domain, important for phase separation. EWSR1 binds to R-loops through its RNA-recognition motif in vitro. Both the domain and motif are required for maintaining CENP-A at the centromere. Therefore, we conclude that EWSR1 guards CENP-A in centromeric chromatins by binding to centromeric RNA.
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•EWSR1 is required to maintain CENP-A at the centromere in interphase cells•EWSR1 binds to CENP-A through the SYGQ2 region, important for phase separation•EWSR1 binds to R loops in vitro through its RNA-recognition motif (RRM)•EWSR1 protects CENP-A in the centromeric chromatin by binding to centromeric RNAs
Kitagawa et al. report a novel mechanism for maintaining the position of the centromere on the chromosome, i.e., centromere identity. EWSR1 (Ewing sarcoma breakpoint region 1) is required for CENP-A deposition at centromeres by binding to centromeric RNA. EWSR1 guards CENP-A in centromeric chromatin by binding to centromeric RNA.
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