Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways

García‐Echeverría, Carlos

doi:10.1007/s11302-008-9111-5

Cited by 20 publications

(12 citation statements)

References 38 publications

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“…The clinical trial data suggest that there is inter-patient variability, with terminal half-life values that range from 2.5 to 8 d for XL-147 and 2 to 15 h for XL-765. Preliminary signs of exposure-dependent pharmacodynamic modulations (changes in plasma insulin levels) are observed at 30 mg/60 mg for XL-147 and 15 mg/30 mg bid for XL-765 [100] .…”

Section: Current Progress In Clinical Trialsmentioning

confidence: 98%

“…Preclinical studies suggest that XL-147 has a remarkable inhibitory effect on MCF-7 breast cancer cells and A549 lung adenocarcinoma cells [98] . The drug also induces striking tumor regression in breast, lung, ovarian, prostate, and glioma tumors [100] . In combination with several chemotherapeutic agents, XL147 has also shown tumor growth inhibition (Table 2).…”

Section: Current Progress In Clinical Trialsmentioning

confidence: 99%

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PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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Section: Current Progress In Clinical Trialsmentioning

confidence: 98%

Section: Current Progress In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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“…192 A more successful attempt to target RAS signaling pathways has been the development of inhibitors for RTKs. 193 However, the use of these compounds is restricted to patients presenting oncogenic RTK signaling, while patients with tumors expressing an oncogenic mutant form of RAS do not benefit from such compounds because oncogenic RAS acts downstream to circumvent the need for an oncogenic RTK to induce cell proliferation and survival. 194 More recent therapeutic attempts have focused on the inhibition of PI3Ks.…”

Section: Development Of Inhibitorsmentioning

confidence: 99%

RAS Interaction with PI3K: More Than Just Another Effector Pathway

2011

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RAS proteins are small GTPases known for their involvement in oncogenesis: around 25% of human tumors present mutations in a member of this family. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate many cellular functions such as cell proliferation, differentiation, apoptosis, and senescence. Phosphatidylinositol 3-kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. However, it is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro, and more importantly, mice with mutations in the PI3K catalytic subunit p110α that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRASinduced lung tumorigenesis and HRAS-induced skin carcinogenesis. These animals also have a delayed development of the lymphatic vasculature. Many PI3K inhibitors have been developed that are now in clinical trials. However, it is a complex pathway with many feedback loops, and interactions with other pathways make the results of its inhibition hard to predict. Combined therapy with another RAS-regulated pathway such as RAF/MEK/ ERK may be the most effective way to treat cancer, at least in animal models mimicking the human disease. In this review, we will summarize current knowledge about how RAS regulates one of its best-known effectors, PI3K.

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“…by interacting with the binding of ligands to the extracellular domain of the EGFR were established. [13][14][15][16][17] Unfortunately, these therapeutic approaches are frequently compromised by the development of refractory disease, e.g., by increased signaling via a non-targeted member of the ErbB network, receptor transactivation or increased production/release of ligands. [18][19][20][21][22][23][24][25][26] One idea to overcome such a therapeutic resistance is to go for a direct cytolytic approach 27 e.g., T or NK cells genetically modified with chimeric antigen receptors (CARs) directed against EGFR that can destroy EGFR-overexpressing tumor cells.…”

Section: Introductionmentioning

confidence: 99%

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

et al. 2017

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Recent treatments of leukemias with chimeric antigen receptor (CAR) expressing T cells underline their impressive therapeutic potential. However, once adoptively transferred into patients, there is little scope left to shut them down after elimination of tumor cells or in case adverse side effects occur. This becomes of special relevance if they are directed against commonly expressed tumor associated antigens (TAAs) such as receptors of the ErbB family. To overcome this limitation, we recently established a modular CAR platform technology termed UniCAR. UniCARs are not directed against TAAs but instead against a unique peptide epitope on engineered recombinant targeting modules (TMs), which guide them to the target. In the absence of a TM UniCAR T cells are inactive. Thus an interruption of any UniCAR activity requires an elimination of unbound TM and the TM complexed with UniCAR T cells. Elimination of the latter one requires a disassembly of the UniCAR-TM complexes. Here, we describe a first nanobody (nb)-based TM directed against EGFR. The novel TM efficiently retargets UniCAR T cells to EGFR positive tumors and mediates highly efficient target-specific and target-dependent tumor cell lysis both in vitro and in vivo. After radiolabeling of the novel TM with 64 Cu and 68 Ga, we analyzed its biodistribution and clearance as well as the stability of the UniCAR-TM complexes. As expected unbound TM is rapidly eliminated while the elimination of the TM complexed with UniCAR T cells is delayed. Nonetheless, we show that UniCAR-TM complexes dissociate in vitro and in vivo in a concentration-dependent manner in line with the concept of a repeated stop and go retargeting of tumor cells via the UniCAR technology.

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Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways

Cited by 20 publications

References 38 publications

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

RAS Interaction with PI3K: More Than Just Another Effector Pathway

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

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