Strategies to Modulate Apoptosis TRAILR1 Monoclonal Antibody

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This MAb targets TRAILR1 expressed on human cancer cells and induces apoptosis in human tumor cell lines. Although initial studies suggested that TRAIL activation preferentially leads to apoptosis of tumor cells over normal cells, recent data suggest that human hepatocytes may also be sensitive to TRAIL activity.82 Phase I studies are currently in progress.

Antisense Bcl2 Strategies: G3139

G3139 is an antisense phosphorothioate oligonucleotide that suppresses the expression of the antiapoptotic protein Bcl2. Results of a trial of 21 patients with non-Hodgkin's lymphoma treated with subcutaneous G3139 demonstrated a response rate of 14% with a further 43% exhibiting stable disease.83 Phase III trials are in progress.

Strategies Targeting p53: ONYX-015, INGN 201, Nutlins

ONYX-015 is a mutant adenovirus with a loss-of-function mutation of the adenoviral E1B gene product. The wild-type viral gene product E1B inactivates p53. ONYX-015 selectively replicates in p53-deficient tumor cells leading to cytolysis. The virus is unable to replicate in cells with wild-type p53.84 Promising results have been demonstrated in phase I and II trials, and also in combination with chemotherapy agents.85 Regional delivery of ONYX-015 has been attempted in different tumor types. A Phase II trial of intratumoral ONYX-015 in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer demonstrated objective tumor responses with an acceptable toxicity profile.86 Furthermore, biopsies revealed selective adenoviral replication and necrosis within some tumor specimens. Intra-tumoral injection has also been attempted in patients with breast cancer chest wall recurrence. Hepatic artery infusion of ONYX-015 in a Phase I/II study of 35 patients with liver metastases secondary to colorectal carcinoma demonstrated antitumoral activity,87 while a Phase I trial of intraperitoneal regional delivery of ONYX-015 was conducted in refractory ovarian cancer.88

INGN 201 is a replication incompetent adenovirus vector in which the E1 region has been replaced by wild-type p53 gene under the control of a cytomegalovirus promoter. Pre-clinical studies demonstrated anticancer properties in head and neck tumor cell lines and xenografts. A Phase I trial of stereotactic intratumoral injection of INGN 201 into recurrent glioma demonstrated minimal toxicity and the transfer of p53 to astrocytic tumor cells that led to transcriptionally active p53, with upregulation of target genes such as p21clp1 and apoptosis in subsets of cells. Phase II studies in patients with advanced recurrent squamous cell carcinoma of the head and neck treated with intralesional INGN 201 indicate that the virus is well tolerated.89 Disease stabilized in 6 of 17 patients with nonresectable disease, and 2 of 17 patients exhibited partial responses. Paradoxically, efficacy appeared independent of p53 status.

Mdm2 inhibits p53 by promoting p53 nuclear export, impeding the interaction of transcription factors with the activation domain of p53 and triggering the degradation of p53 via the ubiquitin-proteosome pathway. Nutlins are a family of synthetic compounds that can successively displace Mdm2 from the N-terminus of p53, thereby promoting p53 activity.90 This is an exciting technical development for the manipulation of protein-protein interactions by small molecules. Furthermore, it raises the possibility of activating p53 in tumors that retain normal p53, thereby promoting apoptotic pathways.

Targeting Sphingosine Kinase Activity: Phenoxodiol

Sphingosine kinase promotes the activity of the caspase inhibitory proteins XIAP and FLIP. The isoflavone phenoxo-diol targets a regulator of sphingosine kinase thereby reducing XIAP and FLIP activity. Phase Ib/II data have recently been presented demonstrating promising activity of oral phe-noxodiol in hormone refractory prostate cancer and late-stage ovarian cancer refractory to chemotherapy.90,92

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