A phase I safety and pharmacokinetic (PK) study of navitoclax (N) in combination with docetaxel (D) in patients (pts) with solid tumors.

Puglisi, Martina; Doorn, Leni van; Blanco-Codesido, Montserrat; Jonge, Maja J. De; Moran, Kirsty; Yang, Jason; Busman, Todd; Franklin, Cindy; Mabry, Mack; Krivoshik, Andrew; Humerickhouse, Rod; Molife, L Rhoda; Eskens, F.

doi:10.1200/jco.2011.29.15_suppl.2518

Cited by 19 publications

(18 citation statements)

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“…In turn, selective BCL‐2 inhibitor venetoclax was developed for hematological malignancies to protect platelet populations . Navitoclax in combination with docetaxel was also utilized for solid tumors but with a presentation of neutropenia as a side effect . In this regard, Leverson et al.…”

Section: Discussionmentioning

confidence: 99%

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Timuçin

Başağa

Kütük

2018

Medicinal Research Reviews

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Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were discussed. In the first section, the design and development of BCL-2/BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, nonselective and selective targeting of MCL-1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL-2 member inhibitors.

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Section: Discussionmentioning

confidence: 99%

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Timuçin

Başağa

Kütük

2018

Medicinal Research Reviews

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“…(Souers et al, 2013;Vandenberg and Cory, 2013), unlike ABT-737 or ABT-263, both of which induce thrombocytopenia due to their neutralization of BCL-XL in platelets (Mason et al, 2007). Indeed, clinically significant thrombocytopenia (and neutropenia) were observed in a phase I study of ABT-263 in combination with docetaxel in solid tumors (Puglisi et al, 2011). ABT-199 was recently shown to elicit promising tumor responses in BCL-2-dependent hematopoietic malignancies (Davids and Letai, 2013;Green and Walczak, 2013), but its in vivo potency for solid tumors is not known.…”

Section: Bcl-2 and Bcl-xl Expression In Breast Cancer And Primary Xenmentioning

confidence: 99%

Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer

et al. 2013

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The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.

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“…refractory tumours in combination with docetaxel, with acceptable toxicity and few responses (2 PR, 5 SD). 56 2. TRAIL is a pro-apoptotic cytokine belonging to the TNF-a superfamily that inhibits several EWS cell lines in vitro.…”

Section: The Bcl-2 Inhibitors Navitoclax Is Developed In Adultmentioning

confidence: 99%

Targeted therapies for bone sarcomas

Heymann¹,

Rédini²

2013

BoneKEy Reports

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Bone sarcomas include a very large number of tumour subtypes, which originate form bone and more particularly from mesenchymal stem cell lineage. Osteosarcoma, Ewing's sarcoma and chondrosarcoma, the three main bone sarcoma entities develop in a favourable microenvironment composed by bone cells, blood vessels, immune cells, based on the 'seed and soil theory'. Current therapy associates surgery and chemotherapy, however, bone sarcomas remain diseases with high morbidity and mortality especially in children and adolescents. In the past decade, various new therapeutic approaches emerged and target the tumour niche or/and directly the tumour cells by acting on signalling/metabolic pathways involved in cell proliferation, apoptosis or drug resistance. The present review gives a brief overview from basic to clinical assessment of the main targeted therapies of bone sarcoma cells.

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A phase I safety and pharmacokinetic (PK) study of navitoclax (N) in combination with docetaxel (D) in patients (pts) with solid tumors.

Cited by 19 publications

References 0 publications

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer

Targeted therapies for bone sarcomas

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