Staff Writer

In a plenary talk about cancer genomics at this week's 100th Annual Meeting of the American Association for Cancer Research, Eric Lander, founding director of Broad Institute, said he hopes to see complete cancer genome analyses become a routine part of research within five years and a standard of care for patients within 10 years.

Lander specified that his goal was a "hope" rather than a prediction - which some might consider too lofty. But a sampling of data from the AACR conference reveals plenty of progress down the personalized medicine path.

One presentation that garnered attention was that of Translational Genomics Research Institute scientist Daniel Von Hoff, who used molecular profiling to drive treatment decisions for 66 relapsed and refractory cancer patients, resulting in improved progression-free survival for 18 patients.

Von Hoff collected tumor samples from patients with various kinds of metastatic disease who had failed an average of about four prior therapies, although some patients had failed as many as 13 treatments. The samples were analyzed using Target Now, an oncology testing service marketed by Irving, Texas-based Caris Diagnostics Inc.

Through DNA microarray and immunohistochemical analyses, the service was able to identify biomarkers in all patients pointing to the potential utility of various approved drugs.

Of the 66 patients treated according to the biomarker analysis, 18 patients (27 percent) had a clinically significant improvement in progression-free survival (PFS). Additionally 47 patients (71 percent) experienced tumor shrinkage, and six patients (9 percent) experienced dramatic tumor shrinkage.

Other presentations at the conference focused on new ways to identify cancer biomarkers and diagnose cancer.

Life Technologies Corp. subsidiary Applied Biosystems, of Carlsbad, Calif., touted its SOLiD System as a tool for identifying methylation patterns across the genome, which may serve as new cancer biomarkers.

Meanwhile researchers from the University of Southern California and the California Institute of Technology presented data on a new membrane microfilter device to capture and characterize circulating tumor cells in blood samples. The device, which separates tumor cells from normal blood cells based on size, captured tumor cells from blood in 92.9 percent of patients samples, while the current gold standard CellSearch (Johnson and Johnson) caught the cancer in 45.6 percent of the samples.

The researchers said the microfilter device is about three to five years from clinical use.

Also working on blood tests to detect cancer is Alameda, Calif.-based Celera Corp., which presented data on biomarker panels for the detection of lung, prostate and colon cancer.

Celera said its colon cancer test distinguished proximal and distal lesions with 90 percent sensitivity and 93 percent specificity, outperforming the standard fecal occult blood test. In lung cancer, the company's test showed 94 percent sensitivity and 93 percent specificity and distinguished malignant cases from benign lung disease.

For now, most cancer biomarkers are used primarily to monitor disease progression and treatment rather than for diagnosis.

Genentech Inc.'s Herceptin (trastuzumab) for breast cancer and Novartis AG's Gleevec (imatinib) for chronic myeloid leukemia and gastrointestinal stromal tumors are prescribed according to the results of biomarker-based companion diagnostic tests. Additionally, DxS Ltd. is seeking FDA approval of a companion diagnostic to detect KRAS mutation status in colorectal patients considering Amgen Inc.'s Vectibix (panitumumab).

Last fall, biomarker data offered new hope for AstraZeneca plc's EGFR-inhibitor Iressa (gefitinib), which received accelerated approval for lung cancer only to be yanked off the market when it failed to show survival benefit in a confirmatory trial.

A Phase III study of the drug in an enriched population of 1,217 Asian patients expected to be responsive to EGFR inhibitors demonstrated that Iressa monotherapy significantly improved PFS compared to chemotherapy in front-line NSCLC patients with EGFR-activating mutations. In patients without the EGFR mutation, the chemotherapy group had significantly better PFS.

So while Iressa couldn't beat placebo in past studies, in the right patients, it beat standard-of-care chemotherapy.

At the AACR conference, several biotechs presented data from evaluations of drugs in subsets of patients stratified by biomarker analyses.

Cambridge, Mass.-based Ariad Pharmaceuticals Inc. and partner Merck & Co. Inc. presented preclinical data showing that their mTOR inhibitor, deforolimus, had anti-tumor activity in models of non-small-cell lung cancer with a KRAS mutation. An estimated 20 percent of NSCLC patients have KRAS mutations, which cause their tumors to be less responsive to EGFR inhibitors like Tarceva (erlotinib, Genentech Inc. and OSI Pharmaceuticals Inc.).

Ariad said deforolimus showed better tumor inhibition than Tarceva in 84 percent of KRAS mutant cell lines tested and inhibited the growth of Tarceva-resistant, KRAS-mutant tumors in multiple mouse models.

Synta Pharmaceuticals Corp., of Lexington, Mass., also is focusing on Tarceva-resistant lung cancer. The company said its heat shock protein 90 (Hsp90) inhibitor STA-9090 displayed activity against cell lines expressing 17 different EGFR mutations associated with NSCLC, including 10 mutations that conferred resistance to Tarceva. The molecule also showed activity in cancers resistant to Gleevec (imatinib, Novartis AG), Sutent (sunitinib, Pfizer Inc.) and 17-AAG.

In other news from AACR:

• Access Pharmaceuticals Inc., of Dallas, reported preclinical data on the Phase II polymer-based DACH platinum prodrug, ProLindac. The poster showed that ProLindac's polymer carrier is highly bound to circulating plasma proteins with little red blood cell accumulation, resulting in sustained tumor exposure to platinum with lower rates of hematological toxicities.

• AEterna Zentaris Inc., of Quebec City, presented preclinical data showing that its PI3K/Akt inhibitor AEZS-126 had favorable in vitro ADMET properties as well as oral bioavailability and antitumor activity in vivo. A second poster focused on the drug's mechanism of action and inhibition of PI3Ka and Akt phosphorylation.

• AngioChem Inc., of Montreal, presented additional data from two ongoing Phase I/II trials of ANG1005, a taxane derivative conjugated to a peptide vector designed to cross the blood-brain barrier. Five of seven patients with advanced solid tumors and brain metastases who received higher doses of ANG1005 experienced an objective response, including one partial response. Seven of 22 malignant glioma patients who received ANG1005 at sub-therapeutic dose levels experienced an objective response. The drug was well tolerated and did not elicit an immune response or neurotoxicity.

• Ariad Pharmaceuticals Inc., of Cambridge, Mass., discovered an anaplastic lymphoma kinase (ALK) inhibitor that has shown activity in preclinical models of lung cancer, lymphoma and neuroblastoma. The molecule is orally bioavailable and selective for ALK over the highly similar insulin-like growth factor-1 receptor and insulin receptor tyrosine kinase. Ariad said it will choose a lead candidate this quarter and begin investigational new drug application enabling studies.

• Array BioPharma Inc., of Boulder, Colo., presented two abstracts showing both the clinical benefit of ARRY-543 in tumors that signal through multiple ErbB family members, and its efficacy in preclinical models when compared to, and combined with, Herceptin (trastuzumab), Xeloda (capecitabine) and Taxotere (docetaxel). ARRY-543 is an oral, potent tyrosine kinase inhibitor of EGFR, ErbB2, and ErbB4 and is active in a wide range of tumor cell lines. The data suggested that, unlike approved ErbB inhibitors, ARRY-543 has the potential to be active against the entire ErbB family while demonstrating a strong safety profile, the company said.

• Ascenta Therapeutics Inc., of Malvern, Pa., presented data showing that its small-molecule, pro-apoptotic agent AT-406 had single-agent activity in a number of solid tumor cell lines and in several mouse xenograft cancer models. The drug also showed synergy with other anticancer agents and inhibition of Mcl-1 predominant lines, which may be useful in treating neuroblastoma. Clinical trials are slated to begin later this year.

• AVEO Pharmaceuticals Inc., of Cambridge, Mass., presented preclinical data showing that SCH 900105 (AV-299) is efficacious in glioblastoma multiforme, non-small-cell lung cancer and pancreatic cancer models. In the U87 GBM model, SCH 900105 administration resulted in complete regressions even after withdrawal of treatment. In addition, several combination studies with other targeted therapeutics, chemotherapies and anti-angiogenic agents demonstrated additive efficacy in vivo.

• BioAlliance Pharma SA, of Paris, presented results on its plasmid AMEP, for metastatic melanoma, showing that in an in vivo experimental model of invasive melanoma, tumor treatment by plasmid AMEP biotherapy, applied through either intratumoral or intramuscular route, induced a strong tumor growth inhibition (> 95 percent and > 50 percent, respectively). Moreover, preliminary acute toxicology studies showed that the therapy is safe and well tolerated. Preclinical toxicology and biodistribution regulatory studies are under way for submission of the regulatory file for a Phase I trial later this year in metastatic melanoma patients.

• GPC Biotech AG, of Martinsried, Germany, reported that preclinical data on RGB-286638, its multitargeted protein kinase inhibitor, demonstrated in vivo activity in several preclinical models of multiple myeloma. The compound also induced cell death in multiple myeloma cells independent from the p53 status; p53 is a gene involved in the control of cell proliferation. The company said it is designing a Phase I study in patients with hematological tumors, including multiple myeloma. Additionally, preclinical data on RGB-286638 in solid tumor cell lines demonstrated it induces rapid tumor cell killing at very low doses.

• Innate Therapeutics Ltd.. (formerly Virionyx Corp. Ltd.), of Auckland, New Zealand, presented data showing that the microparticle immune response modifier MIS416 significantly reduced the number and size of tumors in preclinical models of lung and breast cancer. The molecule showed activity as a single agent, in combination with radiation and in a cancer vaccine model. MIS416 is a microparticulate formation of TLR-9 and NOD-2 agonists.

• Isis Pharmaceuticals Inc., of Carlsbad, Calif., presented results on antisense inhibition of novel targets that could offer new mechanisms to treat cancer. Research by Isis and its collaborators demonstrated the feasibility of targeting a large noncoding RNA, sigma RNA, also known as Malat-1, that could offer a new therapeutic mechanism to treat disease. Isis also presented preclinical data showing that antisense inhibition of STAT5 resulted in potent anti-tumor activity.

• Keryx Biopharmaceuticals Inc., of New York, presented abstracts showing that in vitro studies in neuroblastoma cell lines indicated that perifosine treatment induced inhibition of Akt phosphorylation, and decreased cell survival. In vivo studies of perifosine treatment led to significant increases in neuroblastoma tumor bearing mouse survival. Investigators said the data indicated that as a single agent, perifosine targets activation of Akt in neuroblastoma cells and xenografts, and significantly inhibits tumor growth.

• Lpath Inc., of San Diego, said data in a mouse model of renal cell carcinoma (RCC) for it leading cancer drug candidate, Asonep, showed it, as a single agent in naïve mice, significantly delayed the progression of disease. The company also reported that a Phase I trial in cancer testing the safety and tolerability has not reported any drug-related serious adverse events, even at the higher doses, and Lpath is now focused on which cancer types to target in its Phase II trials.

• MethylGene Inc., of Montreal, presented preclinical data on MG516, a second-generation kinase inhibitor that targets Ret, c-Met, VEGFR and members of the Eph receptor family. The drug inhibited tumor growth in a range of in vivo models at low, once per day, oral doses and induced tumor regression in some cases. Shares of MethylGene (TSX:MYG) rose C5 cents, or 13 percent, to close at C43 cents Tuesday.

• Peregrine Pharmaceuticals Inc., of Tustin, Calif., reported that two preclinical studies confirmed the immunomodulatory mechanisms contributing to the anti-tumor activity of its phosphatidylserine-targeting antibodies. One study confirmed the antitumor effects and immune stimulating ability of a fully human anti-PS antibody and the other demonstrated the ability of a second fully human anti-PS antibody to stimulate development of a critical component of the adaptive immune system.