Herceptin

Shepard, H M; Pei, Jin; Slamon, Dennis J.; Pirot, Zhu; Maneval, Daniel C.

doi:10.1007/978-3-540-73259-4_9

Cited by 63 publications

(55 citation statements)

References 113 publications

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“…The most common strategy is to inhibit the activities of the agonists upstream of the growth factor receptor tyrosine kinases (GF-RTK). Numerous GF-RTK-specific monoclonal antibodies have been developed, such as herceptin for Her2 and Cetuximab for EGFR [10,11,50,51]. Recently, many small molecular inhibitors targeting intracellular kinases of the PI3K-Akt-mTOR pathway, such as MK2206 for Akt, and AZD8055 for mTOR, were developed ( Fig.…”

Section: Targeting Pi3k-akt-mtor Sensitizes Cancer Cells To Chemothermentioning

confidence: 99%

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Wang¹,

Huang²,

Zhang³

2014

Cellular and Molecular Biology Letters

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telangiectasia and Rad3-related; CDK4/6 -cyclin-dependent kinase 4/6; Chk1 -checkpoint kinase 1; Chk2 -checkpoint kinase 2; FA -Fanconi anemia; FANCD2 -Fanconi anemia group D2; FANCI -Fanconi anemia group I; HR -homologous recombination; ICL -DNA interstrand crosslinker; IGFBP-3 -insulin-like growth factor binding protein 3; IRS -insulin receptor substrate; MAPKmitogen-activated protein kinase; mTOR -mammalian target of rapamycin; NERnucleotide excision repair; PH -pleckstrin homology; PI3K -phosphoinositide 3-kinase; PIP2 -phosphatidylinositol 4,5-phosphate; PIP3 -phosphatidylinositol 3,4,5-trisphosphate; PTEN -phosphatase/tensin homolog deleted on chromosome 10; Rb -retinoblastoma; Rheb -Ras-homolog enriched in brain; RNR -ribonucleotide reductase; RTK -receptor tyrosine kinase; TLS -translesion DNA synthesis; TSC2 -tuberous sclerosis complex-2 Abstract: Radiotherapy and chemotherapeutic agents that damage DNA are the current major non-surgical means of treating cancer. However, many patients develop resistances to chemotherapy drugs in their later lives. The PI3K and Ras signaling pathways are deregulated in most cancers, so molecularly targeting PI3K-Akt or Ras-MAPK signaling sensitizes many cancer types to radiotherapy and chemotherapy, but the underlying molecular mechanisms have yet to be determined. During the multi-step processes of tumorigenesis, cancer cells gain the capability to disrupt the cell cycle checkpoint and increase the activity of CDK4/6 by disrupting the PI3K, Ras, p53, and Rb signaling circuits. Recent advances have demonstrated that PI3K-Akt-mTOR signaling controls FANCD2

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Section: Targeting Pi3k-akt-mtor Sensitizes Cancer Cells To Chemothermentioning

confidence: 99%

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Wang¹,

Huang²,

Zhang³

2014

Cellular and Molecular Biology Letters

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“…Genotypic analysis of individual breast tumors led to the discovery that 25% of breast tumors and 60% of intraductal tumors overexpress the gene encoding the human epidermal growth factor receptor2 (HER2, Neu, ErbB-2, CD340); these tumors are associated with poor prognosis and a higher rate of metastasis (2,3). The development of trastuzumab (Herceptin, Genentech), a monoclonal antibody (mAb) targeting the extracellular domain of HER2, has dramatically improved survival in patients with HER2-positive breast cancer (4,5). Routinely administered in combination with a cytotoxic chemotherapeutic agent, trastuzumab has successfully reduced primary and metastatic HER2-positive tumors, with the exception of brain metastases.…”

Section: Introductionmentioning

confidence: 99%

ANG4043, a Novel Brain-Penetrant Peptide–mAb Conjugate, Is Efficacious against HER2-Positive Intracranial Tumors in Mice

Régina

Demeule

Tripathy

et al. 2015

Molecular Cancer Therapeutics

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Anti-HER2 monoclonal antibodies (mAb) have been shown to reduce tumor size and increase survival in patients with breast cancer, but they are ineffective against brain metastases due to poor brain penetration. In previous studies, we identified a peptide, known as Angiopep-2 (An2), which crosses the blood-brain barrier (BBB) efficiently via receptor-mediated transcytosis, and, when conjugated, endows small molecules and peptides with this property. Extending this strategy to higher molecular weight biologics, we now demonstrate that a conjugate between An2 and an anti-HER2 mAb results in a new chemical entity, ANG4043, which retains in vitro binding affinity for the HER2 receptor and antiproliferative potency against HER2-positive BT-474 breast ductal carcinoma cells. Unlike the native mAb, ANG4043 binds LRP1 clusters and is taken up by LRP1-expressing cells. Measuring brain exposure after intracarotid delivery, we demonstrate that the new An2-mAb conjugate penetrates the BBB with a rate of brain entry (K in ) of 1.6 Â 10 À3 mL/g/s. Finally, in mice with intracranially implanted BT-474 xenografts, systemically administered ANG4043 increases survival. Overall, this study demonstrates that the incorporation of An2 to the anti-HER2 mAb confers properties of increased uptake in brain endothelial cells as well as BBB permeability. These characteristics of ANG4043 result in higher exposure levels in BT-474 brain tumors and prolonged survival following systemic treatment. Moreover, the data further validate the An2-drug conjugation strategy as a way to create brain-penetrant biologics for neuro-oncology and other CNS indications.

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“…HER2-positive breast cancers are characterized by the high-level gene amplification of HER2 oncogene, relatively poor prognosis if untreated, and significant clinical benefit from the HER2-targeting monoclonal antibody Trastuzumab (Herceptin, Genentech; ref. 29). Basal-like breast cancers typically lack expression of HER2, ER, and progesterone receptor and, hence, overlap with tumors immunohistochemically defined as ''triple negative'' tumors (30).…”

Section: Technical Validation Of Arraysmentioning

confidence: 99%

Proteomic analysis of breast cancer molecular subtypes and biomarkers of response to targeted kinase inhibitors using reverse-phase protein microarrays

Boyd

Wu²,

O’Brien

et al. 2008

Molecular Cancer Therapeutics

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Although breast cancer molecular subtypes have been extensively defined by means of gene expression profiling over the past decade, little is known, at the proteomic level, as to how signaling pathways are differentially activated and serve to control proliferation in different breast cancer subtypes. We used reverse-phase protein arrays to examine phosphorylation status of 100 proteins in a panel of 30 breast cancer cell lines and showed distinct pathway activation differences between different subtypes that are not obvious from previous gene expression studies. We also show that basal levels of phosphorylation of key signaling nodes may have diagnostic utility in predicting response to selective inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase. Finally, we show that reverse-phase protein arrays allow the parallel analysis of multiple pharmacodynamic biomarkers of response to targeted kinase inhibitors and that inhibitors of epidermal growth factor receptor and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase result in compensatory up-regulation of the phosphatidylinositol 3-kinase/Akt signaling pathway.

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Herceptin

Cited by 63 publications

References 113 publications

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

ANG4043, a Novel Brain-Penetrant Peptide–mAb Conjugate, Is Efficacious against HER2-Positive Intracranial Tumors in Mice

Proteomic analysis of breast cancer molecular subtypes and biomarkers of response to targeted kinase inhibitors using reverse-phase protein microarrays

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