New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.

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On April 20, 2016 Geron Corporation (Nasdaq:GERN) reported two poster presentations of data from non-clinical studies of the telomerase inhibitor, imetelstat, at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held in New Orleans, Louisiana (Press release, Geron, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158608 [SID:1234511145]). The first poster presentation described results that treating acute myeloid leukemia (AML) cell lines with imetelstat enhanced the effects of agents currently used for the treatment of AML. These data extend the rationale from prior non-clinical studies for the potential use of imetelstat in hematologic myeloid malignancies, such as AML, including in combination with standard therapies. The second poster presentation described results from non-clinical studies that provide further evidence of potential on-target mechanisms of telomerase inhibition by imetelstat underlying the reduction in platelets observed in previously conducted imetelstat clinical trials.

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The non-clinical studies were conducted by scientists at Janssen Research & Development, LLC and academic collaborators under the terms of the exclusive worldwide imetelstat license and collaboration agreement between Geron and Janssen Biotech, Inc. The poster presentations are available on Geron’s website at www.geron.com/presentations.

Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines

AML cells express high levels of the telomerase catalytic subunit (hTERT). The expression of hTERT may be regulated through chemical changes to DNA, known as epigenetic modifications, such as the addition of a methyl group (methylation). Non-clinical studies by various cancer biologists have suggested a correlation between hTERT overexpression and hypermethylation in some cancers. Two compounds that are currently used for the treatment of AML, decitabine and 5-azacitidine, act as hypomethylating agents by inhibiting DNA methylating enzymes. Furthermore, these compounds have been reported to also reduce hTERT expression in AML cells in addition to inhibiting cell growth.

The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to determine whether combining hypomethylating agents and imetelstat can further inhibit AML cell viability in vitro compared with either agent alone. Combination treatment of the AML cell lines with either decitabine or 5-azacitidine followed by imetelstat, resulted in a greater reduction in cell viability or slower recovery of growth, respectively, than when a hypomethylating agent was administered alone. Similarly, when AML cell lines were treated with decitabine or 5-azacitidine followed by imetelstat, apoptosis, or cell death, increased in a dose-dependent manner.

Rusbuldt J, et al. 2016 AACR (Free AACR Whitepaper)

Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to trigger innate immune responses. For example, synthetic, single-stranded oligonucleotides with certain properties characteristic of bacteria and virus genomes activate the innate immune response through TLR9 signaling. In addition, TLR activation has been associated with lipopolysaccharide-induced thrombocytopenia in animal models.

The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to test a recent hypothesis that the thrombocytopenia observed in patients with myeloproliferative neoplasms (MPN) treated with imetelstat might occur through off-target effects by binding to and activating TLRs, such as TLR9. Results from the study suggest that the thrombocytopenia associated with imetelstat is not likely to be driven via interactions with TLRs. First, the oligonucleotide imetelstat is shorter and lacks certain features in its sequence required to activate TLR9. Second, in an assay for TLR activity, treatment with imetelstat at clinically relevant concentrations had no stimulatory effect on the majority of TLRs tested, including TLR9. Although a small induction of TLR8 was observed in the assay, such activity was not believed to be relevant because the induction was substantially lower than the positive control used in the experiment, and TLR8 has not been reported to be associated with thrombocytopenia.

The poster also cites results from previous non-clinical studies which suggest potential on-target mechanisms of telomerase inhibition for the observed thrombocytopenia in patients treated with imetelstat. Since telomerase activity is required for the differentiation of megakaryocyte progenitors into mature platelet-producing cells, previous ex vivo studies used cells taken from MPN patients and healthy individuals to show that treatment with imetelstat decreases hTERT expression and inhibits telomerase activity, which is concurrent with blocking the terminal maturation of normal megakaryocyte precursors, reducing the number of mature megakaryocytes available to produce platelets. Other prior ex vivo studies also included in the poster showed that imetelstat selectively inhibits the proliferation of malignant megakaryocyte progenitors from patients with essential thrombocythemia compared to normal progenitors from healthy individuals, suggesting that imetelstat may regulate telomerase differently in malignant versus normal cells.

Baerlocher GM, et al. 2016 AACR (Free AACR Whitepaper)

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting the progenitor cells of the malignant clones associated with hematologic myeloid malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies conducted previously by Geron included fatigue, gastrointestinal symptoms and cytopenias. Patients in those studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.

About the Collaboration with Janssen

On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. Certain regulatory, development, manufacturing and promotional activities are being managed through a joint governance structure, with Janssen responsible for these activities.

Janssen is conducting two imetelstat clinical trials: a Phase 2 clinical trial in patients with intermediate-2 and high risk myelofibrosis (MF) and a Phase 2/3 clinical trial in patients with low and intermediate-1 risk myelodysplastic syndromes (MDS). For more information about these clinical trials, please visit www.clinicaltrials.gov.

On April 20, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of preclinical data relating to its KTN3379 and KTN0073 drug development programs at the AACR (Free AACR Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana, April 16-20, 2016 (Press release, Kolltan Pharmaceuticals, APR 20, 2016, View Source [SID:1234511164]).

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"This new preclinical data with KTN3379, along with emerging clinical results to date, support our plans to initiate a Phase 2 study in squamous cell tumors of the head and neck. Separately, we have identified KTN0073 as a unique antibody targeting the Met receptor tyrosine kinase with novel mechanisms of action. We are actively seeking a partner for the KTN0073 program to assist in the development of this novel and differentiated antibody drug candidate," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

"KTN3379 has shown broad anti-tumor activity in preclinical models, is potent, and binds to a unique epitope on ErbB3 or HER3. We presented scientific data supporting the potential use of KTN3379 for treatment of squamous cell tumors of the head and neck (HNSCC) and we continue to explore additional tumor indications where ErbB3 plays a role in driving the tumor or limiting therapies due to pathway resistance. The data presented shows anti-tumor activity of KTN3379 in HNSCC models in combination with the standard of care, cetuximab and radiation, and the anti-tumor activity correlated with several measurable parameters related to activation of the ErbB3 or EGF receptors. HNSCC cancer enriches for these parameters, and we are measuring these endpoints in ongoing and future clinical studies to guide patient selection and drug effectiveness," said Theresa LaVallee, Ph.D., Senior Vice President, Translational Medicine and Product Development at Kolltan.

Following are key data and results from the four poster presentations at AACR (Free AACR Whitepaper) relating to KTN3379 and KTN0073:

KTN3379
KTN3379 is an IgG1 monoclonal antibody that effectively locks ErbB3 in an inactive conformation by binding to a unique epitope, which may contribute to the antibody’s high potency and dual mechanism of action.

On Monday, April 18, "Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN" (Abstract Number 1196) was presented in a poster session.

The poster presentation reported the following data and results:

ErbB3 and its ligand neuregulin (NRG) are highly expressed in HNSCC and HER2, not EGFR, catalyzes ErbB3 activation in the presence of NRG;

Database analyses of HNSCC patient samples indicated that NRG expression is highly correlated with the expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα), but not other EGFR ligands;

Using NRG-positive cell lines, KTN3379 anti-tumor activity correlated with the level of secreted AREG and TGFα and EGFR homodimer levels; and

The combined measurement of NRG with EGFR activation is a potential biomarker for KTN3379 activity.
On Tuesday, April 19, "Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC" (Abstract Number 2979) was presented in a poster session.

The poster presentation featured the following data and results:

Combined administration of KTN3379 and BYL719, a PIK3Cα inhibitor, enhanced anti-tumor activity over single agent administration in HNSCC models;

Inhibition of PI3K led to upregulation of ErbB3 activity;

ErbB3 upregulation attenuated PI3K inhibition suggesting ErbB3 is playing a role in resistance as a compensatory pathway; and
Dual targeting of the ErbB3 and PI3K pathways led to synergistic anti-tumor activity in vitro and in vivo.

On Tuesday, April 19, "Inhibition of heregulin-mediated ErbB3 signaling as a radiosensitization therapy for head and neck cancers" (Abstract Number 3053) was presented in a poster session.

The poster presentation reported the following data and results:

Two different HNSCC models of cetuximab resistance were generated using A431 and FaDu cell lines by exposure to increasing doses of cetuximab over 14 weeks;

In these models, ErbB3 levels and signaling were upregulated and KTN3379 effectively blocked elevated ErbB3 signaling and overcame the cetuximab resistance in the A431 and FaDu models;

In a panel of six HNSCC cell lines, KTN3379 enhanced the anti-tumor activity of radiation alone or the combination of radiation and cetuximab in most of the cell lines; and

These results suggest that combining KTN3379 with standard of care treatments in HNSCC, including cetuximab and radiation, may enhance anti-tumor activity and may overcome resistance.

KTN0073
KTN0073 is a humanized, IgG2 monoclonal antibody that inhibits Met-dependent tumor growth in preclinical models when activated by HGF, Met gene amplification, or mutations in exon 14.

On Tuesday, April 19, "An anti-Met IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth" (Abstract Number 3835) was presented in a poster session.

The poster presentation highlighted the following data and results:
KTN0073 was identified as a potent anti-Met antibody with broad anti-tumor activity in HGF-driven and Met amplified tumors;

KTN0073 induced potent degradation of oncogenic exon 14-mutant Met, which propagates prolonged Met signaling due to a defect in receptor degradation;

Conversion of the antibody from IgG1 to IgG2 surprisingly resulted in enhanced anti-tumor activity in vitro and in vivo; and

KTN0073 demonstrated broad anti-tumor activity through multiple mechanisms of action in HGF-driven, Met-amplified, and exon 14-mutated tumors.

The posters are available on the Kolltan website.

About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), a receptor tyrosine kinase (RTK) that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers, including head and neck, breast, lung, gastric, and melanoma. Kolltan is conducting multiple clinical trials evaluating KTN3379 in the treatment of solid tumors (NCT02014909, NCT02456701, and NCT02473731).

On April 20, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that data from an investigator-sponsored Phase II study of enzalutamide, an androgen receptor inhibitor, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Medivation, APR 20, 2016, View Source [SID:1234511146]). Preliminary data from a 12-patient subset demonstrated that treatment with enzalutamide alone resulted in potential immune-activating properties in patients with non-metastatic castration sensitive prostate cancer. The primary objective of the study was to evaluate the effect of a short-course of enzalutamide (three months) alone or in combination with a therapeutic cancer vaccine (PROSTVAC) on prostate specific antigen kinetics four months after completing enzalutamide. Data from 12 patients treated with enzalutamide alone was presented by the study’s lead investigator Ravi Madan, M.D., Principal Investigator of the Study and Clinical Director, Genitourinary Malignancies Branch at the National Cancer Institute.

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"Existing literature already suggests that inhibition of androgen receptor signaling can potentiate the function of the thymus and improve the profile of the immune system. These new data suggest that in prostate cancer patients, enzalutamide may also enhance immune cell killing of prostate cancer cells throughout the body," said David Hung M.D., Founder, President and Chief Executive Officer of Medivation. "We are very encouraged by these new data and believe that the potential immune-activating properties of enzalutamide warrant further investigation, particularly in combination with other immunotherapy agents."

The effect of enzalutamide on peripheral immune cells was measured in 12 patients who were receiving enzalutamide alone (160 mg daily for 84 days, without androgen deprivation therapy). Measurements of CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid derived suppressor cells (MDSC), as well as 114 subsets related to immune cell maturation and function, were evaluated. Peripheral blood mononuclear cells were also assessed for T cell receptor excision circles (TREC) to identity recent thymic emigrants and to determine changes in global gene expression.

Results showed that treatment with enzalutamide induced several notable alterations in immune cells consistent with general immune activation. These changes occurred early following treatment, and included an increase in NK cells, decreased frequencies of MDSCs with a suppressive phenotype and decreased frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory checkpoint molecule CTLA4. Additionally, treatment with enzalutamide increased TREC levels by more than 75% in 7 of 12 patients compared with pre-therapy levels (p=0.012). Gene expression analysis of PBMCs corroborated these findings, showing that enzalutamide increased activation of interferon-gamma signaling and related immune-activating pathways. These immune-activating activities for enzalutamide support evaluating the drug in combination with a number of immune-stimulating treatments including checkpoint inhibitors and vaccines.

Enzalutamide is being developed through a collaboration between Medivation and Astellas. Enzalutamide, which is known by the brand name XTANDI, is currently approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

About XTANDI
XTANDI (enzalutamide) capsules is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA. The clinical significance of this MOA is unknown.

XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions ( ≥ 10%) reported from two combined clinical studies that occurred more commonly ( ≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).
Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit View Source

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

On April 20, 2016 Mirna Therapeutics, Inc. (Nasdaq:MIRN), a clinical stage biopharmaceutical company developing a broad pipeline of microRNA-based oncology therapeutics, reported the presentation of new preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Mirna Therapeutics, APR 20, 2016, View Source [SID:1234511166]). Researchers reported results in two poster presentations from experiments demonstrating that the Company’s lead microRNA therapeutic, MRX34 (miR-34), is synergistic with widely used cancer chemotherapies and next-generation tyrosine kinase inhibitors (TKIs).

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"These in vitro data suggest that MRX34 has strong potential in combination with other cancer drugs," commented Miguel Barbosa, Ph.D., Mirna’s Chief Scientific Officer. "The ability of miR-34 to control multiple oncogenic pathways may overcome both primary and acquired resistance when used in combination with chemotherapy or TKIs."

In a poster (#4829) entitled, "miRNA Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Cytotoxic Chemotherapy (CT) in NSCLC," researchers from Mirna and the University of Texas Health Science Center at San Antonio reported:

Synergistic anticancer effects were observed between miR-34a and platinum and other commonly used cytotoxic chemotherapy drugs, across a range of non-small cell lung cancer (NSCLC) cell lines with varying degrees of resistance.
The synergy observed suggests the potential for lower, less toxic doses of chemotherapy than currently used in the clinic when in combination with miR-34a.
In a second poster (#4814) entitled, "MicroRNA (miRNA) Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Next Generation EGFR Tyrosine Kinase Inhibitors (TKIs) in NSCLC," researchers from Mirna reported:

Synergistic anticancer effects were shown between miR-34a and next-generation EGFR TKIs afatinib and rociletinib against a range of wild-type and mutant NSCLC cell lines. These results extend similar findings with the first-generation EGFR TKI erlotinib (Zhao et al, PLoS ONE 9(2):e89105).
Results support the potential of MRX34 and EGFR TKI combinations to overcome both primary and acquired resistance to EGFR TKIs in patients with NSCLC.
Mirna is a grant recipient of the Cancer Prevention Research Institute of Texas (CPRIT) for preclinical and clinical testing of microRNA and targeted drug combination therapies, and also of the National Institutes of Health (NIH) for the study of combination molecular therapies for lung cancer, as well as miRNAs in combination with standard of care chemotherapy.

The posters may be accessed from the Events & Presentations section of the Company’s website.