Hybridon Inc. was busy at the 94th American Association for Cancer Research meeting in Washington, highlighting early stage products.
Its synthetic immunomodulatory oligonucleotides (IMO) were the focus of two presentations, showing that in preclinical studies the compounds demonstrated immunological activity and antitumor activity. More specifically, results showed the IMO compounds have a Th-1-type cytokine induction profile in cell-based assays following in vivo administration in mice.
Selected IMO compounds showed in vivo activity in syngeneic melanoma in a MetaMouse model and in human tumor xenografts in mice of lung, colon, prostate, breast and glioblastoma. Also, in selected tumor models the IMO compounds showed enhanced antitumor activity in combination with chemotherapeutic agents. Pharmacokinetics in tumor-bearing mice showed tissue distribution patterns following intravenous, subcutaneous and intraperitoneal administration, it said.
Separately, Hybridon said it made three presentations on its antisense compound targeted against the Mdm2 oncogene. In the first study, treatment in combination with gefitinib (Iressa) inhibited hormone-refractory cancer cell growth in vitro, with inhibition of Mdm2, Akt and MAPK expression; reduced phosphorylation of Rb; and increased p53 expression. Administration of both agents to nude mice with PC-3 xenografts produced a cooperative antitumor effect. Analysis of tumor samples revealed inhibition of Mdm2, MAPK and VEGF expression and induction of p27.
In the second study, treatment with Hybridon's antisense compound targeted against Mdm2 enhanced radiation sensitization in a variety of human tumor cells and xenografts including lung, prostate, breast and pancreas, through p53-dependent and independent mechanisms.
In the third study, inhibition of Mdm2 protein in LNCaP human prostate cancer cell lines and xenografts resulted in upregulation of p53, p21, Bax and pRb and decreases in Bcl2, ppRb and E2F1 levels. In DU145 human prostate cells, p21 levels were increased. With PC-3 human prostate cells and xenografts, protein levels of p21, Bax and pRb were elevated and pprB and E2F1 levels were decreased.
In other news from the meeting:
Arius Research Inc., of Toronto, reported preclinical study results on two new antibodies, AR7BD-33-11A and AR1A245.6. Both antibodies prevent breast and prostate cancer tumors from growing in prevention models of human cancer, it said. AR7BD-33-11A was also able to stop the growth of existing tumors, while AR1A245.6 slowed growth significantly. Also, animals treated with the antibodies survived longer than those that weren't.
AVI BioPharma Inc., of Portland, Ore., presented preclinical data evaluating the effectiveness of its Neugene antisense drug for prostate cancer. The presentation described a study that evaluated the effectiveness of Neugene antisense drug in inhibiting expression of the matrix metalloproteinase 9 gene. Results from the study showed that the Neugene inhibited MMP-9 gene expression, decreased tumor growth and reduced the formation of new blood vessels associated with the tumor. Further, researchers observed no toxicity or mortality in mice treated with the Neugene.
BioNumerik Pharmaceuticals Inc., of San Antonio, presented data verifying additional mechanisms by which Tavocept appears to exert its chemoprotective effects for taxane and platinum drugs. BioNumerik presented data on the binding preferences and intracellular distribution of Karenitecin (BNP1350) and other compounds in the camptothecin class. Because the mechanisms of action for camptothecins have not been fully determined, the data reported by BioNumerik might be helpful in developing an understanding of the cellular actions of camptothecins and in explaining and addressing the limitations of existing camptothecin drugs, it said.
Dendreon Corp., of Seattle, presented a summary of results from its completed Phase III trial of Provenge, its therapeutic vaccine for prostate cancer. The double-blind, placebo-controlled Phase III trial, D9901, was conducted in men with metastatic, androgen-independent prostate cancer. The results of the trial showed clinical benefit for men with a Gleason score of 7 or less. A Phase III trial of Provenge, D9902B, is under way at medical centers in the U.S., based on the earlier results. To be eligible for the study, patients must have metastatic prostate cancer that has progressed following hormone therapy and have a Gleason score of 7 or less. (See BioWorld Today, Dec. 6, 2002.)
Introgen Therapeutics Inc., of Austin, Texas, said preclinical research that suggests INGN 241, its mda-7 therapeutic, exhibits tumor selectivity in prostate cancer cells, was not toxic to normal cells and might be a possible treatment for prostate cancer was published in the 2nd edition of the 2003 Proceedings of the AACR. Also, it reported results from a preclinical study that suggest INGN 241, its mda-7 therapeutic, could be combined with radiation therapy and shows promise as a possible treatment for lung cancer.
NeoPharm Inc., of Lake Forest, Ill., presented new preclinical data for LEP-ETU (liposomal paclitaxel) and three posters that reported preclinical data for LE-SN38, its NeoLipid liposomal formulation of SN38, the active metabolite of the cancer drug CPT-11. The LEP-ETU data described anticancer effects of LEP-ETU against several different mouse tumor models, including human ovarian, lung, breast, prostate and murine melanoma in comparison to Taxol. The three LE-SN38 posters described in vitro and in vivo studies of LE-SN38 in several human and mouse cell lines, including colon, lung, breast, ovarian and leukemia, and demonstrated enhanced cytotoxicity in vitro and enhanced therapeutic efficacy in vivo in comparison to CPT-11.