News Summaries-February 2010
Additional news items are summarized in the News Module and News Archives (Requires Login).
Researchers at UCLA's Jonsson Comprehensive Cancer Center performed the first complete genomic sequencing of a brain cancer cell line. Sequencing of the extensively studied U87 cell line may lead to better ways of identifying drug targets and in developing in vitro tests to monitor patients to establish treatment results and brain cancer recurrence (news link). The study was published in PLOS Genetics.
The European Commission approved Roche's anticancer drug Herceptin (trastuzumab), in combination with chemotherapy incorporating a fluoropyrimidine and a platinum-based drug, for the treatment of patients with inoperable locally advanced, recurrent, and/or metastatic, HEr2-positive stomach cancer. The approval is based on the results from the international ToGA trial (protocol ID: BO18255; NCT01041404) according to which the overall survival of patients with tumors expressing high levels of HEr2 treated with Herceptin was 16 months compared to 11.8 months among those treated with chemotherapy alone.
St. Jude Children's Research Hospital and Washington University School of Medicine (St. Louis, MO) joined forces to decode the genomes of more than 600 children who have contributed tumor samples for this project. The St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project, estimated to cost $65 million over 3 years, is the largest investment to date aimed at understanding the genetic origins of childhood cancer. The project will sequence the entire genomes of both normal and cancer cells from each patient, comparing differences in the DNA to identify genetic errors that lead to cancer (news link).
According to results reported in January 2010, at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer, from the phase II clinical trial with ASA404 (vadimezan) in combination with standard chemotherapy in patients with either squamous or non-squamous non-small cell lung cancer (nsclc), median OS was 14 months in the ASA404 plus chemotherapy arm compared to 8.8 months in the chemotherapy alone arm. One of the advantages of AS404 is that it is effective and well tolerated regardless of nsclc histology. ASA404 is in development by Novartis and Antisoma.
Abbott received European regulatory approval for the Architect human epididymis protein 4 (HE4) test for the diagnosis of ovarian cancer and it is now available in Europe. The Architect HE4 immunoassay is a simple blood test that, combined with other tests such as the CA125 assay, may aid in determining the risk of whether a pelvic mass is benign or malignant. Abbott partnered with Fujirebio Diagnostics in the development of the assay. The test is also available in some countries in Asia Pacific and Latin America, and was recently submitted to the FDA for 510(k) clearance. The Architect HE4 is one of numerous other in vitro tests (IVT) in ovarian cancer being developed by at least 30 companies
The first patient was enrolled in a phase I clinical trial (protocol ID: 2009_698, MK2206-010; NCT01021748) combining two novel targeted anticancer agents, Merck's Akt inhibitor MK-2206 and AstraZeneca's MEK inhibitor AZD6244 (ARRY-886), based on preclinical evidence indicating that this combination would enhance their anticancer properties. This is one of a few trials combining two novel agents at their early stage of development, particularly by two separate companies. Usually, combinations of novel anticancer agents are evaluated in clinical trials when at least one is at a late stage of development or has already received marketing approval.
In vitro Assessments/Novel Targets
CD200, a negative regulator of the immune system
Normally expected innate immune responses against malignant cells are prevented by negative regulation of the immune system by the tumor itself. CD200 has been identified among effectors used by tumors to suppress T-cell-mediated immune responses in both hematologic malignancies and solid tumors. Therefore, inhibition of CD200 appears to be a potential therapeutic strategy for a variety of malignancies and is currently being evaluated in clinical trials.
In vitro tests (IVT) in ovarian cancer
Over 30 companies are developing in vitro tests in ovarian cancer for early diagnosis and further assessment of disease status, to select patients and/or assess tumor sensitivity for certain treatments, for treatment/disease monitoring, etc. In addition, many trials evaluating novel targeted agents in clinical development in ovarian cancer are using some type of biomarker to select patients, assess drug effectiveness, and interpret results.
Myriad Pharmaceuticals is developing MPI-0485520 and other inhibitors of IKKE, a recently identified oncogene playing a role in controlling proliferation of certain cancer cells through regulation of constitutive NFkappaB activity.
Midkine is a heparin-binding growth factor with mitogenic activity for fibroblasts and neuroectoderm cells. This multifunctional cytokine is expressed during midgestation but is highly restricted in normal adult tissues. Midkine's role in early cancer formation has been validated in clinical studies. Midkine levels in the circulation are greatly elevated in the early stages of cancer formation and high midkine levels have been linked to poor prognosis in numerous malignancies.
Chromosomal rearrangements enhance the activity of receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) and are implicated in various malignancies, including non-Hodgkin's lymphoma (NHL), neuroblastoma and non-small cell lung cancer (nsclc).
Additional items are summarized in the In Vitro Assessments/Novel Targets page.
Special Report
PARP Inhibitors and Synthetic Lethality
Poly(ADP-ribose) polymerase-1 (PARP1) is an abundant nuclear enzyme which promotes the repair of DNA breaks. Inhibition of PARP1, and hence of DNA repair, enhances the efficacy of certain anticancer agents. It is an attractive anticancer target as it participates in mechanisms involved in most solid tumors that may be the key culprits of resistance to most anticancer agents.
PARP1 is one of the most effective participants in DNA repair; it is a component of the DNA base excision repair (BER) protein complex that includes DNA ligase III, XRCC1 and DNA polymerase U. There are about 1 to 2 million PARP-1 molecules per cell, or one molecule per kilobase of DNA), which are activated 100 to 500-fold by DNA-strand breaks.
In early clinical trials, PARP-1 inhibitors have produced promising results when used in situations involving synthetic lethality, a mechanism well known for a long time but only recently demonstrated in the clinic. To date, at least 6 PARP1 inhibitors have entered the clinic and results are very promising in patients with hereditary breast or ovarian cancer who are carriers of mutations in the BRCA1/2 genes.
BRCA1 and BRCA2 are tumor suppressors that are mutated in cases of hereditary breast, ovarian, and prostate cancer. In their normal state, they are a critical part of the homologous recombination pathway, which fixes double strand DNA breaks impaired in cells carrying mutated versions of these genes. Because of synthetic lethality, tumor cells may survive an impaired BER state or mutated BRCA1/2, but not the combination of both.
Using PARP1 inhibition in this context represents the ultimate approach to targeted anticancer strategy, i.e. targeting only tumor cells carrying the intended homozygous mutation. PARP1 inhibitors should not affect normal cells with redundant DNA repair mechanisms, including heterozygous BRCA1/2 cells carrying one normal and one mutant BRCA allele.
Now that it has been demonstrated that this strategy works in patients with homozygous mutations in BRCA1/2 resulting in an impaired homologous recombination pathway, assays are needed to detect such impairments in other tumor types to expand the utility of PARP1 inhibitors.
Over 210 Novel Targeted Agents Have Entered Phase I Clinical Trials
Over 210 targeted agents have entered phase I clinical development with many probably proceeding to phase II. These drugs target 161 molecular moieties from highly specialized ones found in narrow cancer indications to pathways active in most major malignancies.
The recent marketing authorization granted by the European Commission to AstraZeneca's gefitinib (Iressa) for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (nsclc) with activating mutations of epidermal growth factor receptor-tyrosine kinase (EGFr-TK), across all lines of therapy, is a watershed event with far reaching implications as to how new drugs enter the market and how they are used in the clinical setting. With this approval, patients with EGFr mutation-positive tumors may be offered an effective and better tolerated alternative to chemotherapy as a first line treatment.
Conceivably, this approval paves the way for drug therapy in cancer that would require companion in vitro tests to select highly homogenous patient populations with tumors expressing markers specifically targeted by the drugs in question, creating new challenges and opportunities in the way anticancer agents are developed, approved, and used in the clinic.
Parenthetically, UK health authorities known for restrictive reimbursement regulations regarding the use of novel, approved anticancer drugs, are proposing a program to provide experimental drugs with phase III data, to selected populations with refractory late stage disease, before such drugs obtain formal marketing authorization. Such availability may not only help patients with no remaining options but also expand the pool of patients treated with the drugs outside the formal trial process, thus providing additional data as to the drug‘s effectiveness.
ErbB Pathway Inhibitors in Clinical Trials
At least 22 inhibitors of the ErbB pathway are currently in clinical development (excludes immunoconjugates, vaccines, etc.) with 4 having entered phase III clinical trials in a variety of indications. One agent in late stage development is Wyeth's neratinib (HKI-272) in phase III clinical trials in breast cancer.
Clinical Trials of Combinations of Approved ErbB-pathway Inhibitors with Novel Agents
Despite the incredible effort invested in the development of targeted therapeutics addressing the ErbB pathway, first generation drugs have minimal antitumor effects as monotherapies in the majority of patients with advanced malignancies. Most approved indications combine these inhibitors with approved cytotoxic agents. Also, over 1,200 trials have been initiated worldwide with ErbB pathway inhibitors with about 50% of these still ongoing. The majority of these are combination trials with other approved drugs, including targeted drugs and standard cytotoxics. Various molecular moieties and pathways are also being considered as potential combination strategies to enhance the sensitivity of cancer cells to ErbB inhibitors. This report describes various approaches combining ErbB pathway inhibitors with novel targeted agents in development.
Cancer Clinical Pipeline Updates
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The CytRx Pipeline in Oncology
As of January 2010, CytRx had 2 new and 1 marketed anticancer drug in clinical development and was planning multiple phase II clinical trials in both solid tumors and hematologic malignancies.
The Clavis Pharma Pipeline
Clavis Pharma is developing three distinct anticancer agents, two in clincial trials and one in preclinical evaluation. A recent partnering agreement with Clovis Oncology is accelerating development of its CP-4126, a lipid formulation of gemitabine for the treatment of pancreatic cancer. The mechanism of action of CP-4126 may overcome cancer cell resistance that commonly develops with gemcitabine. A test is in development to classify patients according to the expression of the hENT1 (human equilibrative nucleoside transporter 1) pancreatic tumor protein, a cell membrane transporter believed to be critical for gemcitabine entry into tumor cells; CP-4126 enters and kills tumor cells in a hENT1-independent manner.
The AstraZeneca Oncology Pipeline
AstraZeneca has a well balanced clinical pipeline in oncology with 15 novel agents in clinical development, mostly targeted small molecule and biologic inhibitors. Targets include aurora B (STK12/Aurora-1); CD22; checkpoint 1 (Chk1); endothelin receptor type A (EDNRA), ETAr; ephrin type A receptor 2 (EphA2); epidermal growth factor receptor (EGFr ); HEr2/neu; HEr3; insulin-like growth factor 1 (IGF1); insulin-like growth factor 2 (IGF2); mammalian target of rapamycin (mTOR); mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinases (MEK); platelet-derived growth factor receptor alpha (PDGFrA); poly (ADP-ribose) polymerase (PARP); Src (c-src, ASV); Abl; vascular endothelial growth factor receptor (VEGFr) and VEGFr2; RET; glial cell-line derived neurotrophic factor receptor (GDNFr); and c-Kit. The pipeline consists of agents in all stages of development with one, Zactima (vandetanib), having been filed with the FDA and the EMEA, but sinsce withdrawn, for use in combination with chemotherapy for the treatment of advanced non-small cell lung cancer (nsclc) in patients previously treated with one anticancer therapy (second line); AstraZeneca will await results from ongoing trials to decide refiling for approval. The pipeline includes 3 agents having advanced to phase III development; 8 of the 15 agents are in early phase I development.
The NeoPharm Pipeline
The Bristol-Myers Squibb Pipeline
Bristol-Myers Squibb (BMS) agreed to acquire Medarex for $16.00 per share in cash for an aggregate purchase price of approximately $2.4 billion. The acquisition will broaden BMS' current pipeline of anticancer drugs in clinical trials by the addition of several anticancer agents in clinical development in the Medarex pipeline, and bring the late stage anticancer agent ipilimumab in-house. In addition, Medarex has several agents in preclinical development and has over the years forged many collaborations based on its monoclonal antibody (MAb) technology platform that may result in milestones and royalties down the line.
The Novartis Pipeline
In addition to several approved oncology-related drugs, Novartis has one of the broadest pipelines of novel anticancer drugs in clinical development with the majority being targeted agents in early clinical development. Targets addressed include BRaf (B-Raf); CRaf (C-Raf, RAF1); vascular endothelial growth factor (VEGF) receptor 2 (VEGFr2, Flk1, KDR); CD40; colony stimulating factor 1 (macrophage), CSF1; Dickkopf-1 (DKK1); fms-like tyrosine kinase 3 (FLT3); c-Kit; platelet-derived growth factor receptor beta (PDGFrB, PDGFr); protein kinase C (PKC); heat-shock protein 90 (hsp90); histone deacetylase (HDAC); inhibitor of apoptosis (IAP); mammalian target of rapamycin (mTOR); phosphatidylinositol 3`kinase (PI3K); smoothened (SMO); somatotropin release inhibiting factor receptor (SRIFr); insulin-like growth factor 1 (IGF1); and fibroblast growth factor receptor 3 (FGFr3).
The Amgen Pipeline
Amgen is clinically evaluating 7 anticancer agents targeting a variety of markers including hepatocyte growth factor/scatter factor (HGF/SF),
hepatocyte growth factor receptor (HGFr)/c-Met, HEr3 (ErbB3), insulin-like growth factor 1 receptor (IGF1r), Tie-2, angiopoietin-1 and 2, tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAILr2), vascular endothelial growth factor (VEGF) receptor 1 (VEGFr1), VEGFr2, VEGFr3, platelet-derived growth factor receptor beta (PDGFrB), Kit, and RET. The company's strategy in the oncology sector is to pursue agents with broad anticancer activity, primarily angiogenesis inhibitors and apoptosis inducers/enhancers. In addition, Amgen submitted for FDA approval its drug denosumab, an investigational RANK Ligand inhibitor for the treatment and prevention of postmenopausal osteoporosis as well as bone loss in patients undergoing hormone ablation therapy for either prostate or breast cancer.
The Pfizer Pipeline
Pfizer has one of the most diverse pipelines of oncology drugs with 21 agents in clinical development for numerous indications including breast, pancreatic, prostate, and thyroid cancer, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), renal cell cancer (CRC), soft-tissue sarcoma, malignant melanoma, leukemia/lymphoma, multiple myeloma, and myelodysplastic syndrome (MDS), among others. Agents in the pipeline include 4 immunotherapies; 6 monoclonal antibody (MAb)-based agents; and 12 small molecule drugs. A unique feature of the pipeline is its breath of targets, with 20 agents targeting various molecular markers including Activin A receptor type II-like 1 (ACVrL1), ALK1; Anaplastic lymphoma kinase (ALK); Angiopoietin-2 (Ang2); Aurora A (Aurora-2); Aurora B (STK12/Aurora-1); c-Kit; Cadherin 3, type 1 (CDH3), P-cadherin; CD40; Checkpoint 1 (Chk1); Cyclin-dependent kinase 4 (CDK4); CTLA4; EGFr, ErbB1; HEr2 (ErbB2); HEr3 (ErbB3); HEr4 (ErbB4); Focal adhesion kinase (FAK); Hsp90; Insulin-like growth factor 1 receptor (IGF1r)); Met [hepatocyte growth factor receptor (HGFr); Notch 1 (TAN1); Poly (ADP-ribose) polymerase (PARP); Toll-like receptor 9 (TLr9); Vascular endothelial growth factor (VEGF) receptor 2 (VEGFr2, KDR); Platelet-derived growth factor receptor alpha (PDGFrA); PDGFr; and Fms-like tyrosine kinase 3 (FLT3). Although the majority of agents (13/21) are in phase I clinical trials, 7 drugs are in phase II/III clinical trials. Sutent (sunitinib), Pfizer’s proprietary drug on the market, approved for the treatment of refractory gastrointestinal stromal tumors (GIST), and as first line treatment in metastatic renal carcinoma (RCC), generated global revenues of $847 million in 2008. Sutent is in phase II and phase III clinical trials in numerous indications including breast, colorectal, gastric, prostate, liver, and lung cancer. Upon its acquisition, Wyeth’s Torisel (temsirolimus) whose global sales were $122 million in 2008, will boost the group’s oncology related sales derived from novel agents.
The Human Genome Sciences Pipeline
The GPC Biotech/Agennix Pipeline
The Micromet Pipeline
The Bavarian Nordic Cancer Vaccine Pipeline
The Enzon Pharmaceuticals Pipeline
The EntreMed Pipeline
The AVEO Pharmaceuticals Pipeline
The Exelixis Pipeline
The Curis Pipeline
Additional items are summarized in the Cancer Pipeline Updates (Requires Login).
Novel Anticancer Agents
In a report published in the journal Natural Products, investigators at Uppsala University, in Sweden, report that cardiac glycosides, among them oleandrin, proscillaridin A, digitoxin and digoxin, exhibit cytotoxic activity against colon cancer in combination with any of four clinically relevant cytotoxic drugs, 5-fluorouracil, oxaliplatin, cisplatin, or irinotecan.
Aflibercept (VEGF Trap), under development by Regeneron Pharmaceuticals and sanofi-aventis, is an inhibitor of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in late stage development in various malignancies. As of November 2009, three phase III clinical trials, in lung, colorectal and prostate cancer were >80% enrolled with results anticipated by mid-2010 and early 2011. Regeneron and sanofi-aventis also expanded and extended their existing global collaboration to discover, develop, and commercialize fully human therapeutic monoclonal antibodies (MAb) with the annual funding commitment by sanofi-aventis to increase from $100 million to $160 million beginning in 2010, and the research funding to extend through 2017.
In October 2009, Arzerra (ofatumumab) received accelerated approval from the FDA for use in patients with chronic lymphocytic leukemia (CLL) that is refractory to treatment with fludarabine and alemtuzumab. The drug is being commercialized by GlaxoSmithKline under a global license from Genmab. Arzerra is a monoclonal antibody (MAb) that attaches to the small and large loop epitopes on CD20 found on the surface of B-cells, and recruits the body's natural defenses to attack and kill these selected cells that are implicated in cancer, and autoimmune and inflammatory diseases. Arzerra is one of several approaches currently in development for the treatment of CLL, an incurable hematologic malignancy (see http://www.ncbi.nlm.nih.gov/pubmed/19619273?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=9). Arzerra is in development for other indications, mostly in combination with other approved agents.
Supportive Care
Denosumab (Prolia), under development by Amgen, is the first fully human monoclonal antibody (MAb) in late stage clinical development that specifically targets RANK Ligand (RANKL), an essential regulator of osteoclasts, the cells that break down bone. Among other indications, Prolia is being investigated for the treatment and prevention of bone loss resulting from hormone ablation in patients with breast and prostate cancer, as well as for its potential to delay bone metastases and inhibit and treat bone destruction in patients with multiple myeloma and across many stages of cancer. In direct evaluation against zoledronic acid (Zometa; Novartis), the current standard of treatment of bone loss associated with cancer metastasized to the bone, denosumab was superior to Zometa in preventing skeletal related events (SRE) and delayed worsening of bone pain in a phase III clinical trial of 2,046 patients with advanced breast cancer. In addition, denosumab also presented some potential tolerability advantages for many patients, including a lower incidence of renal toxicity and acute phase reactions, combined with the convenience of a monthly SC injection. Similarly, in another phase III clinical trial, denosumab was non-inferior to Zometa in the treatment of bone metastases in 1,776 patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
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