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here's a new one--using herceptin to target a bacterial toxin to her2+ bc tumor cells
Scientists Developing New Therapy for HER2-Positive Breast Cancer
[American Association for Cancer Research]
PHILADELPHIA — Patients with HER2-positive breast cancer may have an alternative therapy when they develop resistance to trastuzumab, also known as Herceptin, according to a laboratory finding published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
Jacek Capala, Ph.D., D.Sc., an investigator at the National Cancer Institute, and colleagues designed, produced and tested HER2-Affitoxin, a novel protein that combines HER2-specific affibody molecules and a modified bacterial toxin, PE38.
"Unlike the current HER2-targeted therapeutics, such as Herceptin, this protein does not interfere with the HER2 signaling pathway but, instead, uses HER2 as a target to deliver a modified form of bacterial toxin specifically to the HER2-positive cancer cells. When cells absorb the toxin, it interferes with protein production and, thereby, kills them," said Capala.
At least, that is what happened in Capala's laboratory. After Affitoxin was injected into tumor-bearing mice, even relatively large, aggressive tumors stopped growing and most of them disappeared. The effect was strong enough that Capala believes it warrants a clinical trial.
"Herceptin has revolutionized the treatment of patients with HER2-positive breast cancer, but a significant number of tumors acquire resistance to the drug," said Capala. "Affitoxin could offer another therapeutic option for those patients whose tumors no longer respond to Herceptin."
ABSTRACT: HER2-Affitoxin: A Potent Therapeutic Agent for the Treatment of HER2-Overexpressing Tumors
[Clinical Cancer Research]
Purpose: Cancers overexpressing the HER2/neu gene are usually more aggressive and are associated with poor prognosis. Although trastuzumab has significantly improved the outcome, many tumors do not respond or acquire resistance to current therapies. To provide an alternative HER2-targeted therapy, we have developed and characterized a novel recombinant protein combining an HER2-specific Affibody and modified Pseudomonas aeruginosa exotoxin A (PE 38), which, after binding to HER2, is internalized and delivered to the cytosol of the tumor cell, where it blocks protein synthesis by ADP ribosylation of eEF-2.
Experimental Design: The effect of the Affitoxin on cell viability was assessed using CellTiter-Glo (Promega). To assess HER2-specific efficacy, athymic nude mice bearing BT-474 breast cancer, SK-OV-3 ovarian cancer, and NCI-N87 gastric carcinoma xenografts were treated with the Affitoxin (HER2- or Tag-specific), which was injected every third day. Affitoxin immunogenicity in female BALB/c mice was investigated using standard antibody production and splenocyte proliferation assays.
Results:In vitro experiments proved that HER2-Affitoxin is a potent agent that eliminates HER2-overexpressing cells at low picomolar concentrations. Therapeutic efficacy studies showed complete eradication of relatively large BT-474 tumors and significant effects on SK-OV-3 and NCI-N87 tumors. HER2-Affitoxin cleared quickly from circulation (T1/2 < 10 minutes) and was well tolerated by mice at doses of 0.5 mg/kg and below. Immunogenicity studies indicated that HER2-Affitoxin induced antibody development after the third injected dose.
Conclusions: Our findings showed that HER2-Affitoxin is an effective anticancer agent and a potential candidate for clinical studies.
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