Engineered Bacteria for Cancer Therapy


A few years ago, scientists explored the idea of making bacteria seek out certain other cells.They engineered the microbes to display antibodies on their surface. However, it is difficult to get the cells to deliver antibodies to their surfaces. Scientists then learned about adhesins. Adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces. The adhesins contain an antibody-like moiety that targets antigens on other cells. In order to kill tumor cells or deliver drugs, scientists want to deploy engineered microbes to specific parts of the body. Researchers have now designed a way to target bacteria to particular surfaces by modifying sticky proteins on the microbes’ surfaces.

The researchers built a synthetic adhesin with an antibody that binds to green fluorescent protein (GFP). They incorporated the new adhesin’s gene into the chromosome of E. coli, along with a gene for a bioluminescent protein. The bacteria’s targets were human cancer cells that the researchers modified to express GFP on their surfaces. After mixing the human and bacterial cells together, the team inspected the cells with fluorescence imaging and found that the bacteria colonized the cancer cells. Bacteria without the synthetic adhesin did not adhere to the human cells.

However, the researchers still need to demonstrate safety and that the bacteria can be engineered to target real-world cancer cell proteins. Scientists are currently developing synthetic adhesins that target proteins in bladder and gastrointestinal cancers. These diseases represent what may be the safest application of this technology because they occur in parts of the body normally inhabited by bacteria.

High-Dose Myeloma Therapy part3


Use of active surveillance for localized prostate cancer varied substantially by demographics and geography. From 2004 to 2007, use of active surveillance versus watchful waiting increased from 9.7% to 15.3%. Increased use of active surveillance was associated with higher socioeconomic status (SES) and white race. Older age, comorbidities, and high-risk tumor characteristics were associated with a reduced likelihood that a man would enter active surveillance.

As a result of widespread use of PSA screening tests, the vast majority of newly diagnosed prostate cancers are early-stage, localized disease. Though some of the patients will benefit from immediate treatment, most of the cancers are not life threatening.  In response to concerns about overtreatment of prostate cancer, many medical centers have established active surveillance protocols to distinguish between indolent and clinically significant cancers. However, no standard protocol exists, clinical guidelines provide limited direction for patient selection, and use of active surveillance remained poorly understood.

To examine trends in active surveillance, Filson and colleagues analyzed Medicare-linked data from the National Cancer Institute’s Surveillance for the years 2004 to 2007. They identified all patients who did not have definitive treatment within 12 months of diagnosis and evaluated factors associated with use of active surveillance.

The authors found that use of active surveillance decreased with increasing patient age, number of comorbid conditions, and tumor risk. Although use of active surveillance varied significantly by geography, the authors could find no market-specific characteristics associated with active surveillance.

The authors concluded that future research should seek to quantify patient and provider contributions to the variation, identify facilitators and barriers to use of active surveillance, identify factors associated with racial variations, and use other data sources to improve understanding of variations in use of active surveillance across insurance plans and age groups.

 

High-Dose Myeloma Therapy part2


Neoadjuvant chemoradiation did not improve outcomes in early-stage esophageal cancer and was associated with significantly higher postoperative mortality, results of a randomized phase III trial showed.

Patients who received neoadjuvant therapy had a 3-year survival of 47.5% compared with 53.0% for patients who had surgery without preoperative chemoradiation. The rate of complete resection did not differ significantly between treatment groups. However, postoperative mortality was three times higher in patients who received neoadjuvant therapy.

Neoadjuvant chemoradiation is used frequently in the treatment of locally advanced esophageal cancer, but its utility in early disease has remained unclear. To address the issue, investigators at 30 French centers randomized 195 patients with stage I or II esophageal cancer to surgery alone or preoperative cisplatin-5FU chemoradiation followed by surgery.

The primary endpoint was overall survival. Secondary endpoints included disease-free survival, postoperative morbidity, in-hospital mortality, complete resection, and prognostic factors. An interim analysis suggested futility in demonstrating a significant advantage of neoadjuvant therapy, and the trial ended prematurely.

Stage distribution of the patient population was stage I in 19% of cases, IIa in 53.3%, and IIb in 27.7%. Complete resection occurred in 93.8% of patients randomized to neoadjuvant therapy and 92.1% in patients who received surgery without preceding therapy.

With respect to other secondary endpoints, in-hospital mortality was 11.1% in the neoadjuvant therapy group and 3.4% in the surgery-alone group. Causes of postoperative death in the patients who received preoperative therapy were one case each of aortic rupture, chylothorax, anastomotic leak, gastric conduit necrosis, mesenteric and lower limb ischemia, and two cases each of acute respiratory distress syndrome and undetermined despite autopsy.

 

A Potential Drug Target for Alzheimer’s Disease part2


First described in 1906 by Alois Alzheimer, Alzheimer’s disease (AD) represents the most common form of dementia today and the sixth leading cause of death in the United States (Alzheimer’s Association). Symptomatically, this fatal neurodegenerative disorder is most often characterized by loss of memory and decreased abilities in orientation and reasoning. Pathological features of AD include the presence of neurofibrillary tangles (NFTs) and plaques that are formed as a result of accumulation of β-amyloid peptide (Aβ; a proteolytic product of amyloid precursor protein [APP] by secretases). More than 20 million people worldwide currently suffer from this incurable disease, with more than 5 million in the United States. Various factors contributing to AD pathogenesis are being explored, but mechanisms leading to AD remain elusive.

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From a drug discovery point of view, several potential targets within the amyloid pathways have been proposed for AD treatment. For example, Fyn, a Src family kinase, is thought to be involved in AD by its manipulated expression level in a transgenic mouse model of AD (Yang et al., J Alzheimers Dis 2011;27:243–252). Association of Fyn to Aβ is also supported by protection against Aβ-mediated toxicity observed in mature hippocampal cells from Fyn−/− mice. On the other hand, it is also thought that Aβ, particularly the soluble Aβ oligomers, are important pathogenic structures in AD, and thus, targeting soluble Aβ oligomers is considered an optimal intervention approach. In this aspect, drug discovery efforts have been placed on generation of antibodies that bind to Aβ oligomers with high specificity and affinity, modulators that efficiently block oligomer assembly, and selective antagonists for neuronal receptors (Hefti et al., Trends Pharmacol Sci 2013;34(5):261–266).

A Potential Drug Target for Alzheimer’s Disease part1


Joshi and co-workers show in this research article data suggesting that Golgi is a potential drug target for AD. In this study, APPswe/PS1ΔE9, a widely used AD transgenic mouse model was utilized, expressing an APP Swedish mutation and the exon 9 deletion mutant of human PS1. Initially, it was demonstrated that Golgi fragmentation occurred in this transgenic mouse model, as well as in tissue culture cells that were doubly transfected with cDNAs encoding both mutants. Application of specific protease inhibitors to AD cells led to a pronounced reduction in Golgi fragmentation, strongly illustrating Aβ accumulation as a cause for Golgi fragmentation. What could be the mechanisms for Aβ-mediated Golgi fragmentation?

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As kinase (cyclin-dependent kinase-5, cdk5) activation has been previously reported as a result of Aβ production, Golgi fragmentation was subsequently reduced in the current study upon the addition of kinase inhibitors to AD cells. The highly organized stacked Golgi structure is supported by several Golgi structural proteins, such as GRASP65, an important component tethering the cisternae into stacks and a major mitotic kinase target.

The authors further found that GRASP65 was highly phosphorylated in AD cells through immunoprecipitation and Western blot studies, and GRASP65 phosphorylation was due to cdk5 that was activated by Aβ accumulation. After identification and confirmation of Golgi fragmentation mechanism, nonphosphorylatable mutants of GRASP proteins were transfected in AD cells, and Golgi structure and function were rescued. This proof-of-principle study points to molecular causes for Golgi fragmentation and also a potential new target for AD treatment.

Ganetespib into Phase 3 Extension of AML LI-1 Study part1


AML is a rapidly progressing hematologic cancer characterized by uncontrolled proliferation of immature blast cells in the bone marrow. The American Cancer Society estimates there will be approximately 18,860 new cases of AML and approximately 10,460 deaths in the U.S. in 2014. AML patients with relapsed or refractory disease and newly diagnosed AML patients over 60 years of age with poor prognostic risk factors typically die within one year, resulting in an acute need for new treatment options for these patients.

MDS is a hematopoietic stem cell neoplasm characterized by disordered and ineffective hematopoiesis which results in irreversible decline in the number and quality of blood-forming cells. Patients often develop severe anemia requiring frequent blood transfusions. In most cases progressive bone marrow failure results in neutropenia and thrombocytopenia, and in about one third of patients the disease progresses into AML, usually within a few years.

Ganetespib, an investigational drug candidate, is a selective inhibitor of heat shock protein 90 (Hsp90), a molecular chaperone which controls the folding and activation of a number of client proteins that drive tumor development and progression. Many solid and hematologic tumors are dependent on Hsp90 client proteins including proteins involved in “oncogene addiction” (ALK, HER2, mutant BRAF and EGFR, androgen receptor, estrogen receptor, and JAK2); proteins involved in resistance to chemotherapy and radiation therapy (ATR, BCL2, BRCA1/2, CDK1/4, CHK1, survivin, and WEE1); proteins involved in angiogenesis (HIF-1alpha, VEGFR, PDFGR, and VEGF); and proteins involved in metastasis (MET, RAF, AKT, MMPs, HIF-1alpha, and IGF-1R). In preclinical models, inhibition of Hsp90 by ganetespib results in the inactivation, destabilization, and eventual degradation of these cancer-promoting proteins. Ganetespib is being evaluated in trials in lung cancer, breast cancer, and other tumor types. The most common adverse event seen to date has been transient, mild or moderate diarrhea, which has been manageable with standard supportive care. Ganetespib has received Fast Track designation from FDA for second-line treatment of non-small cell lung adenocarcinoma in combination with docetaxel.

Ganetespib into Phase 3 Extension of AML LI-1 Study part2


Synta Pharmaceuticals Corp. announced the advancement of ganetespib into the Phase 3 extension of the AML LI-1 trial. AML LI-1 is a multicenter, randomized Phase 2/3 clinical study evaluating several novel treatment regimens, including the combination of ganetespib with low dose cytarabine (Ara-C), in newly diagnosed elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who are not eligible for intensive chemotherapy. Ganetespib is a next-generation inhibitor of the chaperone protein Hsp90, which is critical for the activation and stability of numerous proteins that drive cancer growth and proliferation. Ganetespib has been studied in over 1000 patients to date.

Advancement into the Phase 3 extension follows an interim analysis of results from 50 patients who received the ganetespib-cytarabine combination in the Phase 2 portion of the trial. The primary efficacy outcome in Phase 2 was rate of complete response. Per protocol, the Phase 3 extension will include an interim futility analysis and enroll approximately 200 patients in the ganetespib-cytarabine and the cytarabine alone arms, for a total of approximately 400 patients. The primary efficacy endpoint for the Phase 3 extension will include overall survival. The Company is currently in discussion with study investigators, and anticipates providing additional details, including the timing of study milestones, as they become formalized.

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The AML LI-1 trial is the first of three multicenter, randomized studies supported by the Leukemia & Lymphoma Research Fund and Cancer Research UK to include a ganetespib treatment arm. AML LI-1 is being conducted under the auspices of the UK’s National Cancer Research Institute (NCRI) Haematological Oncology Study Group, with investigators in Denmark, France, New Zealand, and the UK, and under the sponsorship of Cardiff University, UK. The other two studies, to be initiated later this year, are the AML-18 trial, evaluating ganetespib with standard DA (daunorubin and Ara-C) in patients over 60 years old who can tolerate intensive chemotherapy, and the AML-19 trial, evaluating ganetespib in combination with conventional chemotherapy in younger patients with AML.

AML LI-1’s ‘pick-the-winner’ trial design is intended to rapidly assess new therapeutics with the potential to improve outcomes in very difficult to treat patients with AML and MDS.  Ganetespib’s progress in the AML LI-1 study underscores the potential of Hsp90 inhibition across a broad range of cancers

Keryx Receives FDA Fast Track Designation for KRX-0401 (Perifosine) for the Treatment of Relapsed/Refractory Multiple Myeloma


Keryx Biopharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for KRX-0401 (perifosine), the Company’s novel, potentially first-in-class, oral anti-cancer agent that inhibits the phosphoinositide 3-kinase (PI3K)/Akt pathway, for the treatment of relapsed/refractory multiple myeloma.

The Fast Track program of the FDA is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Fast Track designated drugs ordinarily qualify for priority review, thereby expediting the FDA review process.

A Phase 3 trial investigating perifosine in combination with bortezomib (VELCADE®) and dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma is expected to commence by year-end under a Special Protocol Assessment (SPA) with the FDA. In addition, in September, the Company announced that perifosine had received Orphan-Drug designation in the United States for the treatment of multiple myeloma.

Ron Bentsur, Chief Executive Officer of Keryx Biopharmaceuticals, commented, “This Fast Track designation can significantly reduce the FDA review time of a new drug application, and therefore can expedite the time to market for perifosine in multiple myeloma.” Mr. Bentsur added, “We believe that the Fast Track designation, together with the SPA and Orphan Drug status previously granted to us by the FDA for perifosine in multiple myeloma, significantly enhances the value proposition of perifosine in this indication. We are eager to begin the Phase 3 trial later this month.”

KRX-0401 (perifosine) is in-licensed by Keryx from AeternaZentaris, Inc. in the United States, Canada and Mexico.

The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells


Multiple myeloma (MM) is a B-cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required.

We report the antimyeloma effect of NVP-AEW541, a small molecule that belongs to the pyrrolo[2,3-d]pyrimidine class, identified as a selective inhibitor of the insulin-like growth factor-I receptor (IGF-IR) in vitro kinase activity. NVP-AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP-AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP-AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP-AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP-AEW541 provoked a marked cell cycle blockade accompanied by pRbdownregulation. Interestingly, NVP-AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP-AEW541 induced cell death through caspase-dependent and -independent mechanisms. All these data, suggest the potential effect of IGF-IR kinase inhibitors as therapeutic agents for MM patients.

A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson’s disease

Abnormal motor behaviors in Parkinson’s disease (PD) result from striatal dysfunction due to an imbalance between dopamine and glutamate transmissions that are integrated by dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). c-Abelson tyrosine kinase (c-Abl) phosphorylatescyclin-dependent kinase 5 (Cdk5) at Tyr15 to increase the activity of Cdk5, which reduces the efficacy of dopaminergic signaling by phosphorylating DARPP-32 at Thr75 in the striatum. Here, we report that in the mouse striatum, a novel c-Abl inhibitor, nilotinib (AMN107), inhibits phosphorylation of both Cdk5 at Tyr15 and DARPP-32 at Thr75, which is negatively regulated by dopamine receptor activation through a D2 receptor-mediated mechanism. Like a D2-agonist, nilotinib synergizes with a D1-agonist for inducing striatal c-Fos expression. Moreover, systemic administration of nilotinib normalizes striatal motor behaviors in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings suggest that nilotinib could possibly serve as a new and alternative agent for treating PD motor symptoms.