Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors.
SIGNIFICANCE: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer.
Moreover, TSSC promoted solid tumor cell apoptosis, upregulated the protein expression of Bax, and downregulated the protein expression of Bcl-2 in response to regulate apoptosis of cancer cells in mice bearing hepatoma 22 solid tumors.
<b>Purpose:</b> Clinically available BH3 mimetic drugs targeting BCLXL and/or BCL2 (navitoclax and venetoclax, respectively) are effective in some hematologic malignancies, but have limited efficacy in solid tumors.
The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias.
Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2 family dynamics.
Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors.
A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors.
ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors.
A phase I pharmacokinetic and pharmacodynamic correlative study of the antisense Bcl-2 oligonucleotide g3139, in combination with carboplatin and paclitaxel, in patients with advanced solid tumors.
As a strategy for blocking Bcl-2 for enhancement of the chemotherapeutic effect, antisense Bcl-2 (AS Bcl-2; G3139, oblimersen sodium, Genasense) has shown promise, and there are several ongoing clinical studies with hematological malignancies as well as solid tumors.
A Bcl-2 antagonist, ABT-737, has recently been discovered and shown to induce regression of solid tumors, but its activity is limited to a fraction of small-cell lung carcinoma (SCLC) models tested.
Constitutive overexpression of Bcl-2 or unchanged expression after treatment with anticancer drugs confers drug resistance not only to hematologic malignancies but also to solid tumors.
Immunohistochemical detection of bcl-2 products and in situ estimation of DNA fragmentation during apoptosis by the nick and labelling method were performed to establish any correlation between these two apparently opposing processes in human solid tumors.
The expression of bcl-2 protein has been observed in most follicular lymphomas and in approximately 25% of high-grade non-Hodgkin's lymphomas, as well as in solid tumors such as carcinomas of the lung, prostate, and nasopharynx.