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Rajendran P.,National University of Singapore | Ong T.H.,Humphrey Oei Institute | Chen L.,National University of Singapore | Li F.,National University of Singapore | And 12 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third cause of global cancer mortality. Increasing evidence suggest that STAT3 is a critical mediator of oncogenic signaling in HCC and controls the expression of several genes involved in proliferation, survival, metastasis, and angiogenesis. Thus, the novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC. Experimental Design: The effect of butein on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was investigated. The in vivo effect of butein on the growth of human HCC xenograft tumors in male athymic nu/nu mice was also examined. Results: We tested an agent, butein, for its ability to suppress STAT3 activation in HCC cells and nude mice model along with prospectively testing the hypothesis of STAT3 inhibition in a virtual predictive functional proteomics tumor pathway technology platform. We found that butein inhibited both constitutive and inducible STAT3 activation in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src and Janus-activated kinase 2. Butein inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. When administered intraperitoneally, butein inhibited the growth of human HCC xenograft tumors in male athymic nu/nu mice. Conclusions: Overall, cumulative results from experimental and predictive studies suggest that butein exerts its antiproliferative and proapoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo. ©2010 AACR.


NEWTOWN, Pa. and SAN JOSE, Calif., Dec. 06, 2016 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer and Cellworks, a customized therapy design company that improves clinical outcomes and creates value for pharma, payers and physicians, today announced the presentation of their collaborative effort to identify higher-risk MDS (HR-MDS) patients that are likely to respond to rigosertib at the 2016 ASH Annual Meeting in San Diego California, taking place December 3-6, 2016. The presentation by Dr. Guillermo Garcia-Manero from the MD Anderson Cancer Center, lead investigator from the ONTME trial, used Cellworks’ proprietary bio-simulation platform to retrospectively correlate clinical benefit to IV rigosertib treatment in the Phase 3 ONTIME study in HR-MDS patients with molecular and cytogenetic data. This computer simulation led to the characterization of certain biological pathways that predict response to IV rigosertib in HR-MDS patients. Notably, patients with these predictive biological pathways also shared common cytogenetic abnormalities – trisomy of chromosomes 8 and 21 – that correlated with positive clinical outcome in ONTIME. “This retrospective analysis of ONTIME has helped identify biological factors related to clinical outcomes to treatment with IV rigosertib,” stated Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the study.  “These results confirm prior studies where patients with certain cytogenetic abnormalities were sensitive to IV rigosertib. These data also reinforce the clinical strategy of the ongoing Phase 3 INSPIRE trial to target only the highest-risk MDS patients with rigosertib.” “We are excited by this use of our proprietary bio-simulation platform to predict response to novel therapeutics in a heterogeneous disease like HR-MDS,” commented Yatin Mundkur, CEO of Cellworks.  “Among other applications, the Cellworks platform is intended to inform the design of Phase 2 and 3 clinical trials by establishing and validating inclusion criteria.  In this case, we are pleased that this analysis has validated enrollment criteria for Onconova’s Phase 3 INSPIRE trial.” The poster entitled “Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response,” was presented on December 5, 2016 at the ASH Annual Meeting in San Diego, California.  A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website. Onconova Therapeutics is a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova's clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. The Company’s most advanced product candidate, rigosertib, is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf and PI3 kinases. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.  In addition to rigosertib, two other candidates are in the clinical stage, and several candidates are in pre-clinical stages.  For more information, please visit http://www.onconova.com. The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trial involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 global INSPIRE trial as 2nd-line treatment for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is suited for patients with advanced disease and provides long duration of exposure and ensures adequate dosing under a controlled setting. The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the  U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial.  INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment.  This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.  The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care.  The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443). Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. These statements relate to future events or Onconova Therapeutics, Inc.'s future operations, clinical development of Onconova's product candidates and presentation of data with respect thereto, regulatory approvals, expectations regarding the sufficiency of Onconova's cash and other resources to fund operating expenses and capital expenditures, Onconova's anticipated milestones and future expectations and plans and prospects. Although Onconova believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Onconova has attempted to identify forward-looking statements by terminology including “believes,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “should,” “approximately” or other words that convey uncertainty of future events or outcomes. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Onconova’s need for additional financing and current plans and future needs to scale back operations if adequate financing is not obtained, the success and timing of Onconova’s clinical trials and regulatory approval of protocols, and those discussed under the heading “Risk Factors” in Onconova’s most recent Annual Report on Form 10-K and quarterly reports on Form 10-Q. Any forward-looking statements contained in this release speak only as of its date. Onconova undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.


NEWTOWN, Pa. and SAN JOSE, Calif., Dec. 06, 2016 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer and Cellworks, a customized therapy design company that improves clinical outcomes and creates value for pharma, payers and physicians, today announced the presentation of their collaborative effort to identify higher-risk MDS (HR-MDS) patients that are likely to respond to rigosertib at the 2016 ASH Annual Meeting in San Diego California, taking place December 3-6, 2016. The presentation by Dr. Guillermo Garcia-Manero from the MD Anderson Cancer Center, lead investigator from the ONTME trial, used Cellworks’ proprietary bio-simulation platform to retrospectively correlate clinical benefit to IV rigosertib treatment in the Phase 3 ONTIME study in HR-MDS patients with molecular and cytogenetic data. This computer simulation led to the characterization of certain biological pathways that predict response to IV rigosertib in HR-MDS patients. Notably, patients with these predictive biological pathways also shared common cytogenetic abnormalities – trisomy of chromosomes 8 and 21 – that correlated with positive clinical outcome in ONTIME. “This retrospective analysis of ONTIME has helped identify biological factors related to clinical outcomes to treatment with IV rigosertib,” stated Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the study.  “These results confirm prior studies where patients with certain cytogenetic abnormalities were sensitive to IV rigosertib. These data also reinforce the clinical strategy of the ongoing Phase 3 INSPIRE trial to target only the highest-risk MDS patients with rigosertib.” “We are excited by this use of our proprietary bio-simulation platform to predict response to novel therapeutics in a heterogeneous disease like HR-MDS,” commented Yatin Mundkur, CEO of Cellworks.  “Among other applications, the Cellworks platform is intended to inform the design of Phase 2 and 3 clinical trials by establishing and validating inclusion criteria.  In this case, we are pleased that this analysis has validated enrollment criteria for Onconova’s Phase 3 INSPIRE trial.” The poster entitled “Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response,” was presented on December 5, 2016 at the ASH Annual Meeting in San Diego, California.  A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website. Onconova Therapeutics is a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova's clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. The Company’s most advanced product candidate, rigosertib, is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf and PI3 kinases. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.  In addition to rigosertib, two other candidates are in the clinical stage, and several candidates are in pre-clinical stages.  For more information, please visit http://www.onconova.com. The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trial involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 global INSPIRE trial as 2nd-line treatment for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is suited for patients with advanced disease and provides long duration of exposure and ensures adequate dosing under a controlled setting. The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the  U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial.  INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment.  This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.  The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care.  The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443). Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. These statements relate to future events or Onconova Therapeutics, Inc.'s future operations, clinical development of Onconova's product candidates and presentation of data with respect thereto, regulatory approvals, expectations regarding the sufficiency of Onconova's cash and other resources to fund operating expenses and capital expenditures, Onconova's anticipated milestones and future expectations and plans and prospects. Although Onconova believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Onconova has attempted to identify forward-looking statements by terminology including “believes,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “should,” “approximately” or other words that convey uncertainty of future events or outcomes. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Onconova’s need for additional financing and current plans and future needs to scale back operations if adequate financing is not obtained, the success and timing of Onconova’s clinical trials and regulatory approval of protocols, and those discussed under the heading “Risk Factors” in Onconova’s most recent Annual Report on Form 10-K and quarterly reports on Form 10-Q. Any forward-looking statements contained in this release speak only as of its date. Onconova undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.


NEWTOWN, Pa. and SAN JOSE, Calif., Dec. 06, 2016 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer and Cellworks, a customized therapy design company that improves clinical outcomes and creates value for pharma, payers and physicians, today announced the presentation of their collaborative effort to identify higher-risk MDS (HR-MDS) patients that are likely to respond to rigosertib at the 2016 ASH Annual Meeting in San Diego California, taking place December 3-6, 2016. The presentation by Dr. Guillermo Garcia-Manero from the MD Anderson Cancer Center, lead investigator from the ONTME trial, used Cellworks’ proprietary bio-simulation platform to retrospectively correlate clinical benefit to IV rigosertib treatment in the Phase 3 ONTIME study in HR-MDS patients with molecular and cytogenetic data. This computer simulation led to the characterization of certain biological pathways that predict response to IV rigosertib in HR-MDS patients. Notably, patients with these predictive biological pathways also shared common cytogenetic abnormalities – trisomy of chromosomes 8 and 21 – that correlated with positive clinical outcome in ONTIME. “This retrospective analysis of ONTIME has helped identify biological factors related to clinical outcomes to treatment with IV rigosertib,” stated Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the study.  “These results confirm prior studies where patients with certain cytogenetic abnormalities were sensitive to IV rigosertib. These data also reinforce the clinical strategy of the ongoing Phase 3 INSPIRE trial to target only the highest-risk MDS patients with rigosertib.” “We are excited by this use of our proprietary bio-simulation platform to predict response to novel therapeutics in a heterogeneous disease like HR-MDS,” commented Yatin Mundkur, CEO of Cellworks.  “Among other applications, the Cellworks platform is intended to inform the design of Phase 2 and 3 clinical trials by establishing and validating inclusion criteria.  In this case, we are pleased that this analysis has validated enrollment criteria for Onconova’s Phase 3 INSPIRE trial.” The poster entitled “Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response,” was presented on December 5, 2016 at the ASH Annual Meeting in San Diego, California.  A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website. Onconova Therapeutics is a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova's clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. The Company’s most advanced product candidate, rigosertib, is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf and PI3 kinases. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.  In addition to rigosertib, two other candidates are in the clinical stage, and several candidates are in pre-clinical stages.  For more information, please visit http://www.onconova.com. The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trial involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 global INSPIRE trial as 2nd-line treatment for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is suited for patients with advanced disease and provides long duration of exposure and ensures adequate dosing under a controlled setting. The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the  U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial.  INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment.  This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.  The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care.  The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443). Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. These statements relate to future events or Onconova Therapeutics, Inc.'s future operations, clinical development of Onconova's product candidates and presentation of data with respect thereto, regulatory approvals, expectations regarding the sufficiency of Onconova's cash and other resources to fund operating expenses and capital expenditures, Onconova's anticipated milestones and future expectations and plans and prospects. Although Onconova believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Onconova has attempted to identify forward-looking statements by terminology including “believes,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “should,” “approximately” or other words that convey uncertainty of future events or outcomes. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Onconova’s need for additional financing and current plans and future needs to scale back operations if adequate financing is not obtained, the success and timing of Onconova’s clinical trials and regulatory approval of protocols, and those discussed under the heading “Risk Factors” in Onconova’s most recent Annual Report on Form 10-K and quarterly reports on Form 10-Q. Any forward-looking statements contained in this release speak only as of its date. Onconova undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.


NEWTOWN, Pa. and SAN JOSE, Calif., Dec. 06, 2016 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer and Cellworks, a customized therapy design company that improves clinical outcomes and creates value for pharma, payers and physicians, today announced the presentation of their collaborative effort to identify higher-risk MDS (HR-MDS) patients that are likely to respond to rigosertib at the 2016 ASH Annual Meeting in San Diego California, taking place December 3-6, 2016. The presentation by Dr. Guillermo Garcia-Manero from the MD Anderson Cancer Center, lead investigator from the ONTME trial, used Cellworks’ proprietary bio-simulation platform to retrospectively correlate clinical benefit to IV rigosertib treatment in the Phase 3 ONTIME study in HR-MDS patients with molecular and cytogenetic data. This computer simulation led to the characterization of certain biological pathways that predict response to IV rigosertib in HR-MDS patients. Notably, patients with these predictive biological pathways also shared common cytogenetic abnormalities – trisomy of chromosomes 8 and 21 – that correlated with positive clinical outcome in ONTIME. “This retrospective analysis of ONTIME has helped identify biological factors related to clinical outcomes to treatment with IV rigosertib,” stated Guillermo Garcia-Manero, MD, Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, and lead author of the study.  “These results confirm prior studies where patients with certain cytogenetic abnormalities were sensitive to IV rigosertib. These data also reinforce the clinical strategy of the ongoing Phase 3 INSPIRE trial to target only the highest-risk MDS patients with rigosertib.” “We are excited by this use of our proprietary bio-simulation platform to predict response to novel therapeutics in a heterogeneous disease like HR-MDS,” commented Yatin Mundkur, CEO of Cellworks.  “Among other applications, the Cellworks platform is intended to inform the design of Phase 2 and 3 clinical trials by establishing and validating inclusion criteria.  In this case, we are pleased that this analysis has validated enrollment criteria for Onconova’s Phase 3 INSPIRE trial.” The poster entitled “Computational Analysis of Genomic Abnormalities from a Phase 3 Trial of Rigosertib in Higher-Risk MDS: Simulation of a Predictive Signature for Clinical Response,” was presented on December 5, 2016 at the ASH Annual Meeting in San Diego, California.  A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website. Onconova Therapeutics is a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova's clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. The Company’s most advanced product candidate, rigosertib, is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf and PI3 kinases. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.  In addition to rigosertib, two other candidates are in the clinical stage, and several candidates are in pre-clinical stages.  For more information, please visit http://www.onconova.com. The intravenous form of rigosertib has been employed in Phase 1, 2, and 3 clinical trial involving more than 800 patients, and is currently being evaluated in the randomized Phase 3 global INSPIRE trial as 2nd-line treatment for patients with higher-risk MDS, after failure of hypomethylating agent, or HMA, therapy. This formulation is suited for patients with advanced disease and provides long duration of exposure and ensures adequate dosing under a controlled setting. The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the  U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial.  INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment.  This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.  The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care.  The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443). Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. These statements relate to future events or Onconova Therapeutics, Inc.'s future operations, clinical development of Onconova's product candidates and presentation of data with respect thereto, regulatory approvals, expectations regarding the sufficiency of Onconova's cash and other resources to fund operating expenses and capital expenditures, Onconova's anticipated milestones and future expectations and plans and prospects. Although Onconova believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Onconova has attempted to identify forward-looking statements by terminology including “believes,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “should,” “approximately” or other words that convey uncertainty of future events or outcomes. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Onconova’s need for additional financing and current plans and future needs to scale back operations if adequate financing is not obtained, the success and timing of Onconova’s clinical trials and regulatory approval of protocols, and those discussed under the heading “Risk Factors” in Onconova’s most recent Annual Report on Form 10-K and quarterly reports on Form 10-Q. Any forward-looking statements contained in this release speak only as of its date. Onconova undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.2.3.2-1 | Award Amount: 16.70M | Year: 2011

The More Medicines for Tuberculosis (MM4TB) consortium evolved from the highly successful FP6 project, New Medicines for TB (NM4TB), that delivered a candidate drug for clinical development two years ahead of schedule. Building on these firm foundations and exploiting its proprietary pharmacophores, MM4TB will continue to develop new drugs for TB treatment. An integrated approach will be implemented by a multidisciplinary team that combines some of Europes leading academic TB researchers with two major pharmaceutical companies and four SMEs, all strongly committed to the discovery of anti-infective agents. MM4TB will use a tripartite screening strategy to discover new hits in libraries of natural products and synthetic compounds, while concentrating on both classical and innovative targets that have been pharmacologically validated. Whole cell screens will be conducted against Mycobacterium tuberculosis using in vitro and ex vivo models for active growth, latency and intracellular infection. Hits that are positive in two or more of these models will then be used for target identification using functional genomics technologies including whole genome sequencing and genetic complementation of resistant mutants, yeast three hybrid, click chemistry and proteomics. Targets thus selected will enter assay development, structure determination, fragment-based and rational drug design programs; functionally related targets will be found using metabolic pathway reconstruction. Innovative techniques, based on microfluidics and array platforms, will be used for hit ranking, determining rates of cidality and confirming mechanism of action. Medicinal chemistry will convert leads to molecules with drug-like properties for evaluation of efficacy in different animal models and late preclinical testing.


Almine J.F.,University of Sydney | Wise S.G.,University of Sydney | Wise S.G.,Heart Research Institute | Hiob M.,University of Sydney | And 5 more authors.
FASEB Journal | Year: 2013

Following penetrating injury of the skin, a highly orchestrated and overlapping sequence of events helps to facilitate wound resolution. Inflammation is a hallmark that is initiated early, but the reciprocal relationship between cells and matrix molecules that triggers and maintains inflammation is poorly appreciated. Elastin is enriched in the deep dermis of skin. We propose that deep tissue injury encompasses elastin damage, yielding solubilized elastin that triggers inflammation. As dermal fibroblasts dominate the deep dermis, this means that a direct interaction between elastin sequences and fibroblasts would reveal a proinflammatory signature. Tropoelastin was used as a surrogate for elastin sequences. Tropoelastin triggered fibroblast expression of the metalloelastase MMP-12, which is normally expressed by macrophages. MMP-12 expression increased 1056 ± 286-fold by 6 h and persisted for 24 h. Chemokine expression was more transient, as chemokine C-X-C motif ligand 8 (CXCL8), CXCL1, and CXCL5 transcripts increased 11.8 ± 2.6-, 10.2 ± 0.4-, and 8593 ± 996-fold, respectively, by 6-12 h and then decreased. Through the use of specific inhibitors and protein truncation, we found that transduction of the tropoelastin signal was mediated by the fibroblast elastin binding protein (EBP). In silico modeling using a predictive computational fibroblast model confirmed the up-regulation, and simulations revealed PKA as a key part of the signaling circuit. We tested this prediction with 1 μM PKA inhibitor H-89 and found that 2 h of exposure correspondingly reduced expression of MMP-12 (63.9 ± 12.3%) and all chemokine markers, consistent with the levels seen with EBP inhibition, and validated PKA as a novel node and druggable target to ameliorate the proinflammatory state. A separate trigger that utilized C-terminal RKRK of tropoelastin reduced marker expression to 65.0-76.5% and suggests the parallel involvement of integrin αVβ3. We propose that the solubilization of elastin as a result of dermal damage leads to rapid chemokine up-regulation by fibroblasts that is quenched when exposed elastin is removed by MMP-12.-Almine, J. F., Wise, S. G., Hiob, M., Kumar Singh, N. K., Tiwari, K. K., Vali, S., Abbasi, T., and Weiss, A. S. Elastin sequences trigger transient proinflammatory responses by human dermal fibroblasts. © FASEB.


Werngren J.,Public Health Agency of Sweden | Wijkander M.,Public Health Agency of Sweden | Perskvist N.,Karolinska University Hospital | Balasubramanian V.,Astrazeneca | And 4 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

The MIC of the novel antituberculosis (anti-TB) drug AZD5847 was determined against 146 clinical isolates from diverse geographical regions, including eastern Europe, North America, Africa, and Asia, using the automated Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system. These isolates originated from specimen sources such as sputum, bronchial alveolar lavage fluid, pleural fluid, abscess material, lung biopsies, and feces. The overall MIC90 was 1.0 mg/liter (range, 0.125 to 4 mg/liter). The MICs of AZD5847 for isolates of Mycobacterium tuberculosis were similar among drug-sensitive strains, multidrug-resistant (MDR) strains, and extensively drug resistant (XDR) strains. The good in vitro activity of AZD5847 against M. tuberculosis and the lack of cross-resistance make this agent a promising anti-TB drug candidate. Copyright © 2014 American Society for Microbiology. All Rights Reserved.


The present disclosure describes a composition and a kit having a plurality of compounds for use in the treatment of inflammatory joint diseases and chronic inflammatory connective tissue diseases, such as Rheumatoid Arthritis (RA). The disclosure also relates to a process of obtaining the composition and the method of treating diseases by administration of the compositions.


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