ALTERNATIVE CANCER SOLUTION

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Squalamine Extract

Anti-Angiogenesis
Squalamine was originally discovered in the tissues of the dogfish shark and is part of a class of naturally occurring, pharmacologically active small molecules known as “aminosterols.” Squalamine has exhibited reproducible anti-angiogenic properties in a number of in vitro and in vivo assays, including eye disease and cancer models, across multiple independent laboratories.

Cancer
Squalamine may be potentially useful as an anti-angiogenic therapy for some types of cancer. From research done in cancer, including Phase I and II clinical trials, a significant safety database for squalamine as a single agent and in combination with other agents has been compiled. It appears that squalamine is less toxic and better tolerated than other therapies, not only chemotherapy, but also approved anti-angiogenics.

Squalamine continues to be evaluated in Phase 2 clinical studies for the treatment of solid tumors. Specifically, clinical studies have been performed in prostate cancer and non-small cell lung cancer (NSCLC) to evaluate intravenously administered squalamine in combination with leading chemotherapeutics in each indication. Phase 2 trials in ovarian cancer have also been conducted, as described below.

In November 2001, a Phase 2b trial in non-small cell lung cancer investigated weekly dosing of squalamine in combination with the leading chemotherapeutics.

In November 2002, a $1.1 million award was granted by the United States Department of Defense, Army Medical Research and Materiel Command (USAMRMC) to the University of Chicago, School of Medicine for the first clinical trial of squalamine in the treatment of prostate cancer. The trial is designed as an open-label randomized study to evaluate the activity and tolerability of squalamine in conjunction with anti-androgen therapy in patients undergoing radical prostatectomy. Up to 132 patients will receive weekly dosing of squalamine (100 mg/m2) for either 6 or 12 weeks. The study continues to enroll patients.

In May 2002, Phase 2 trials in recurrent advanced ovarian cancer revealed the following: 35% of evaluable patients (9 of 26) had an objective response to the study drug regimen of squalamine and carboplatin. Best response to therapy has included five complete responses, and four partial responses. The U.S. Food and Drug Administration granted squalamine Orphan Drug designation for the treatment of ovarian cancer in 2001.

Also, in May 2002, positive final results for squalamine in its Phase 2a NSCLC clinical trial were announced. The median survival time for all patients enrolled in the study was 10.0 months (95% confidence interval, 6.6 to 12.3 months). The median survival time for patients receiving the squalamine dose of 300 mg/m2/day was 8.5 months (95% C.I. 6.6 to 17.8 months). The median time to progression was 4.4 months (95% C.I. 3.1 to 6.9 months) for all study patients, 5.5 months for patients in the 300 mg/m2/day group (95% confidence interval 3.2 to 9.4 months).

On June 5, 2004, at the On June 5, 2004, at the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO), updated interim safety and efficacy results from squalamine were presented in a Phase IIB NSCLC clinical trial. This multi-center randomized study enrolled 45 stage IIIB or stage IV advanced lung cancer patients who were to receive weekly dosing of squalamine, combined with weekly chemotherapy of carboplatin and paclitaxel. All 45 patients were evaluated for safety. Overall, the combined drug regimen was well tolerated. Two patients were withdrawn for intercurrent illnesses before receiving any study medication. Of the 43 patients receiving study medications, 21 received a weekly dose of 100 mg/m2, and 22 received a weekly dose of 200 mg/m2 of squalamine. Forty-one patients were evaluable for efficacy. Objective responses occurred in 24% of the patients (10 of 41; 1 complete and 9 partial responses). An objective response is defined as a 50% or greater reduction in tumor size, measured bi-dimensionally by CT scan, lasting 4 weeks, with no new lesions appearing, as rated by the investigators and radiologists. In comparison, the objective response rate was 27% in a prior Phase IIA NSCLC study dosing squalamine daily for five days every three weeks, in combination with carboplatin and paclitaxel every three weeks. In summary, the one year survival rate is 22%, with a 72% overall response rate that include one durable complete response with squalamine combination therapy. Thirteen patients remain alive while progression and survival statistics continue to mature.

Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression.

Dan Li1, Jon I Williams2 and Richard J Pietras1


1UCLA School of Medicine, Department of Medicine, Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center, Los Angeles, California, CA 90095, USA

2Genaera Corporation, Plymouth Meeting, Pennsylvania, PA 19462, USA

Correspondence to: RJ Pietras, Department of Medicine, Division of Hematology-Oncology, 10833 Le Conte Ave., 11-934 Factor Bldg., Los Angeles, CA 90095-1678, USA

Abstract
Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.

Oncogene (2002) 21, 2805-2814. DOI: 10.1038/sj/onc/1205410

To assess the antitumor efficacy of squalamine in human ovarian cancer, a phase II clinical study was performed by Davidson et al. (52). On recruiting 33 patients with stage III or stage IV ovarian cancer who were resistant or refractory to platinum-based chemotherapy, squalamine was administered with carboplatin as a 5-day continuous infusion at a dose of 200 mg/m2/day. Average treatment time was 81 days. Response data have been reported for 22 patients, and, among this group, eight patients had an objective clinical response. Major toxicity reported in this study among three patients was grade 4 thrombocytopenia, anemia, leukopenia, myalgia or asthenia, symptoms often associated with carboplatin chemotherapy. Additional patients were enrolled in the study, but the final data remain to be presented (52). Nonetheless, these results suggest that squalamine may be a significant addition to current treatment options for patients with advanced refractory ovarian cancers. Based on currently-available information on the potential antitumor efficacy of squalamine in ovarian cancer, the antiangiogenic steroid has been designated an ‘orphan drug’ candidate for future therapeutic development in ovarian malignancy, a group for whom new treatment alternatives are urgently needed.

June 4, 2002
Squalamine Yields Positive Results in NSCLC

Scientists from Genaera announced positive final results for squalamine in a phase II non-small cell lung cancer (NSCLC) clinical trial. Dr. Joan Schiller of the University of Wisconsin was the lead researcher.

The multicenter open-label study investigated the preliminary efficacy and safety of squalamine used with first-line standard chemotherapy of carboplatin (Paraplatin) and paclitaxel (Taxol) in patients with stage IIIB or IV advanced disease. The phase IIa NSCLC trial initially enrolled 18 patients with an escalating dose of squalamine from 100 mg/m�/day to 400 mg/m�/day. Researchers then enrolled 27 patients in a second portion of the study at 300 mg/m�/day of squalamine. The patients received up to 6 cycles of carboplatin and paclitaxel every 3 weeks, immediately followed by 5 daily treatments of squalamine every 3 weeks.

For all patients enrolled in the study at all squalamine doses, 27% experienced an objective response. Objective responses were seen in 29% of patients receiving of 300 mg/m�/day of squalamine for one or more cycles of therapy; an appropriate historical benchmark objective response rate for this group of patients treated with carboplatin and paclitaxel alone was 17%, and the median survival time for all patients enrolled was 10.0 months. The median survival time for patients receiving the squalamine dose of 300 mg/m�/day was 8.5 months; again, the historical benchmark objective median survival for this group treated with carboplatin and paclitaxel alone was 8.1 months. The median time to progression was 4.4 months for all patients, 5.5 months for patients in the 300 mg/m�/day group, and 3.1 months in the comparison data.

An ongoing phase IIb study in NSCLC patients is designed to evaluate 90 patients with first-line therapy of 100 mg/m� or 200 mg/m� of squalamine weekly used with weekly carboplatin and paclitaxel.