Scientists from BIND Biosciences Inc., with colleagues from both academia and industry, reported data Wednesday on a targeted therapy, BIND-014, that is able to specifically deliver chemotherapy docetaxel to prostate tumor cells and the vasculature of many different types of solid tumors.
In a late-breaking poster presentation at the American Association for Cancer Research (AACR) meeting in Chicago, BIND-014 demonstrated safety and tolerability, as well as early hints of efficacy, in a Phase I trial.
And in a paper that appeared in the April 5, 2012, issue of Science Translational Medicine, the authors described their approach for making BIND-014 and similar targeted nanoparticles which the authors have termed Accurins and presented preclinical data on the compound.
In contrast to molecularly targeted drugs, which interfere with the action of a specific protein to therapeutic effects, Accurins bind to a specific surface protein to concentrate a drug which itself can be either molecularly targeted or not at the sites where it is needed.
Targeting delivery, BIND CEO Scott Minick told BioWorld Today, allows the drugs to be delivered in much lower doses overall, while it still will be present in higher doses where it is needed. And with that, "you significantly change the pharmacology, and as a result, you change the biology of the drug." For example, in their paper, the researchers described that Accurin-delivered docetaxel kept inhibiting tumor cell growth for up to 24 hours, much longer than solvent-based docetaxel.
In the study whose results were presented at AACR, BIND-014 also showed evidence of antitumor activity in cancers that normally have only a minimal response to docetaxel. In their poster, the researchers reported one durable confirmed partial response in cervical cancer (in which docetaxel is normally ineffective) and five with stabilization of disease, each one in a different type of solid tumor.
Minick said he was happy with the trial's hints at efficacy, particularly since "in these very late-stage, very heavily pretreated patients you don't expect to see much of an efficacy signal."
Many scientists are working on nanospheres to improve drugs. But their utility has been slow to come to fruition, in part because they can vary in a plethora of ways. The Science Translation Medicine paper lists "composition, size, shape, rigidity, surface charge, hydrophilicity, and ligand type and density" for the nanoparticle itself, plus "drug type, solubility, loading and release kinetics" for its payload, all of which interact to affect "immune surveillance, particle extravasation, tissue penetration and cellular uptake."
And then, when you've got your nanoparticle, you have to be able to scale it up.
Minick and his team approached that design headache by what they termed a combinatorial approach, simultaneously varying 10 different parameters and testing more than a hundred different combinations of them. The result was BIND-014, which consists of shell materials PLA, PLGA and PEG that are already used in medical supplies and that the FDA is "very comfortable" with. BIND-014's shell is metabolized to lactic acid, the same substance that is produced in muscles during exercise.
That shell is targeted via ACUPA, which binds to a surface marker that is expressed on prostate cancer cells and the vasculature of most tumor cells. And it is filled with docetaxel, a workhorse chemotherapy approved for prostate, breast and lung cancer.
In animals, the nanoencapsulated docetaxel was active for much longer, and at lower doses, than solvent-based docetaxel. The main goal of the Phase I study, as always, was to establish safety and tolerability. But the authors did see partial responses at doses that were only a fifth of the dose necessary with solvent-based docetaxel, as well as responses in cancers that are normally impervious to docetaxel.
BIND is working on several other Accurins. The company is developing some off-patent drugs on their own, and has three partnerships with biopharmaceutical companies, working on newer, molecularly targeted drugs.
Each Accurin, Minick said, is developed individually. But the approach is "not from scratch in the sense of starting with a chemistry textbook. . . . It is a modular approach, and we have already built many models."
Targeted therapies can carry the seeds of their own demise, since they put evolutionary pressure on the tumor cells to escape. In most tumors, PSMA is expressed on the vasculature, which is not the target of the drug, making such resistance unlikely. An exception to the rule is prostate cancer, where the targeting molecule is on the tumor cells themselves. But, Minick said, to date that concern has remained theoretical. His team has "not seen the tumor mutate in such a way that there is no more PSMA expression."
In other news from AACR:
Ablynx NV, of Ghent, Belgium, reported that tetrameric NanobodyR agonist, TAS266, developed with its Nanobody technology, efficiently targeted death receptor 5 (DR5) across a number of tumor types. That result has not been achieved with conventional monoclonal antibodies. The result was controlled death of cancer cells. Results were presented by partner Novartis AG, of Basel, Switzerland.
Array BioPharma Inc., of Boulder, Colo., said data from a Phase II trial showed that selumetinib, a small-molecule MEK inhibitor, produced a disease control rate, defined as either complete or partial response or progression-free survival or progression-free survival of greater than six months, of 81 percent in women with recurrent low-grade serous ovarian or peritoneal cancer. The 52-patient study was funded by the National Cancer Institute. Selumetinib is licensed to London-based AstraZeneca plc, and top-line results from a Phase II trial testing the drug in combination with dacarbazine in first-line BRAF-mutant melanoma are due later this year.
Caris Life Sciences Inc., of Irving, Texas, presented findings regarding the biological role of circulating microvesicles in the transport and exchange of miRNA, as well as their potential utility as a non-invasive blood-based diagnostic tool.
Cellceutix Corp., of Beverly, Mass., presented preclinical data demonstrating the antitumor effects of cancer drug Kevetrin in several wild-type and mutant p53 tumor xenografts. Data showed the drug targets both MDM2-p53 and Rb-E2F pathways in tumor suppression.
Curis Inc., of Lexington, Mass., presented preclinical data demonstrating antitumor activity of CUDC-907, a dual PI3K and HDAC inhibitor, in hematological cancer models. In in vitro and in vivo testing, CUDC-907 outperformed a first-in-class HDAC inhibitor, as well as an investigational pan-PI3K inhibitor given as a single agent or in a combination of both agents. The drug also demonstrated enhanced antitumor activity in animal models of B-cell lymphoma and multiple myeloma when co-administered with standard-of-care agents.
Cyclacel Pharmaceuticals Inc., of Berkeley Heights, N.J., presented data showing that treatment with sapacitabine's major active metabolite, CNDAC, in colon cancer, ovarian cancer and non-small-cell lung cancer (NSCLC) cell lines after depletion or inactivation of BRCA1 or BRCA2 led to higher rates of cell death vs. control. In addition, CNDAC synergized with either PARP inhibitors or cisplatin in both NSCLC and ovarian cancer cell lines. Data from a separate presentation comparing CNDAC, cytarabine and mitoxantrone activity in acute myeloid leukemia (AML) cell lines, as well as in bone marrow and peripheral blood cells from AML patients, showed that low-dose CNDAC and also mitoxantrone exhibited improved activity and induction of cell death in AML cells lines and patient samples compared to cytarabine. Sapacitabine, an oral nucleoside analogue, is in Phase III testing in elderly patients with newly diagnosed AML.
Immunomedics Inc., of Morris Plains, N.J., reported preclinical data showing that two hR1-derived agents, developed using the company's Dock-and-Lock technology, displayed cell-binding activity comparable to their parental drug, a humanized anti-IGF-1R monoclonal antibody. However, Hex-hR1 , which comprises six antigen-binding regions of hR1 tethered to a common crystallizable region of the antibody, could effectively down-regulate IGF-1R at concentrations 10-fold lower than hR1. All three agents significantly inhibited the growth of two renal cell carcinoma cell lines and demonstrated a synergistic interaction with Torisel (temsirolimus, Pfizer Inc.) at concentrations as low as 1 nanomolar for Hex-hR1, 2.6 nanomolar for 1R-2b, an intact hR1 antibody attached to two molecules of interferon-alpha2b, and 10 nanomolar for hR1.
Noxxon Pharma AG, of Berlin, said NOX-A12 delayed the recurrence of ENU-induced rat brain tumors following irradiation. The combination of NOX-A12 and radiation increased the median life span of the rats from 189 days to 349 days. Noxxon plans to move on to a clinical trial of NOX-A12 in combination with standard therapy in first-line glioblastoma.
Peregrine Pharmaceuticals Inc., of Tustin, Calif., reported data from two Phase I trials of bavitixmab, a phosphatidylserine-targeting monoclonal antibody. In one study with five evaluable patients, testing bavituximab in combination with paclitaxel in HER2-negative metastatic breast cancer, two patients achieved a complete tumor response, one patient achieved a partial response and two had progressive disease. Data from the second study showed that bavituximab plus Nexavar (sorafenib, Bayer AG and Onyx Pharmaceuticals Inc.) in advanced hepatocellular carcinoma patients showed no dose-limiting toxicities or serious adverse events. In a separate poster, the company presented preclinical data showing robust antitumor responses in a prostate cancer model when an animal version of bavituximab was combined with androgen deprivation therapy.
PharmaMar SA, of Madrid, Spain, a subsidiary of Zeltia SA, presented six trials of its cancer candidates Yondelis (trabectedin), Zalypsis and Irvalec. For Yondelis, the company is evaluating whether the status of endonuclease ERCC5 (XPG) is linked to the drug's activity in soft-tissue sarcoma and said new data suggested that may be the case. Other trials further evaluate the activity of Yondelis, and investigate the mechanisms of Zalypsis and Irvalec.
Pieris AG, of Freising, Germany, presented preclinical data for PRS-110, showing significant, dose-dependent tumor growth inhibition. Pieris said the drug is an antagonist of the c-Met receptor and has the ability to inhibit both ligand-dependent and ligand-independent c-Met activation.
Synta Pharmaceuticals Corp., of Lexington, Mass., presented preclinical results for ganetespib, for melanoma and colorectal cancer, showing that the drug is active in tumor cell lines with acquired resistance to BRAF inhibitors. The studies also supported combining ganetespib with other therapies in future trials.