scholarly journals An updated Review on Therapeutic Potential of Entrectinib as a Promising TrK, ROS 1, and ALK Inhibitor in Solid Tumors and Lung Cancer

2021 ◽  
pp. 413-421
Author(s):  
M. Archana ◽  
Mariya Palathingal ◽  
K. Athulya Damodharan ◽  
P. Ashisha ◽  
Nuaman, Akash Marathakam
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Therapeutic Potential ◽  
Current Status ◽  
Anaplastic Lymphoma ◽  
Kinase C ◽  
Fda Approval ◽  
Adults And Children ◽  
Clinical Trails ◽  
Tyrosine Receptor Kinase

Entrectinib is a selective inhibitor of tyrosine kinases , tropomyosin receptor kinases that targets oncogenic rearrangements in Neurotropic Tyrosine Receptor kinase, c-ros oncogene 1 and Anaplastic lymphoma kinase used for the treatment of various solid tumors. Entrectinib gained its first worldwide approval in Japan in June 2019 for the treatment of NTRK fusion-positive, advanced or recurring solid tumours in adults and children. In august 15, 2019 drug got FDA approval for the treatment of solid tumors in adult and children aged 12 and above. This article summarizes current status of Entrectinib from ongoing clinical trails and ideal place for drug in therapy.

2006 RADAR Report Card on Conversion Rates from Accelerated FDA Approval to Regular FDA Approval for Drugs Used To Treat Hematologic Malignancies: Policy Changes Continue To Be Needed.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3318-3318
Author(s):  
Andrew J. Lurie ◽  
Mark V. Mai ◽  
Martin S. Tallman ◽  
June McCoy ◽  
Charles L. Bennett
Keyword(s):  
Imatinib Mesylate ◽  
Solid Tumors ◽  
Trial Design ◽  
Liposomal Doxorubicin ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Cancer Drugs ◽  
Fda Approval ◽  
Conversion Rates

Abstract Background: At ASH 2004 and 2005, we reported < 20% rates of from accelerated approval (AA) to regular approval (RA) for drugs used to treat hematologic malignancies (HMs). The FDA convened Oncologic Drug Advisory Committee (ODAC) meetings with sponsors of these drugs in 2003 and 2005 outlining recommendations for completion of subpart H trials. Congressmen Markey and Hinchey have raised concern over low rates of completion of subpart H studies for all AA drugs. The Research on Adverse Drug Events and Reports (RADAR) project reviewed the current status of subpart H commitments for all cancer drugs that received AA prior to 2005. Methods: NDAs and supplements for new uses from the FDA, package inserts, and literature reviews were reviewed. Results: Of 19 cancer drugs receiving AA prior to 2005, conversion to RA has occurred for 2 of 9 drugs for HMs and 8 of 11 drugs for solid tumors (STs) (22% vs 73%, p<0.05). Subpart H studies have been ongoing for a median of 5 years for AA drugs for HMs; however, for ST drugs, these studies were completed in a median of 2.5 years. Of 7 subpart H studies reviewed at the 2005 ODAC meeting on AA, subpart H evaluations continue for all 4 for HMs versus 1 of 3 for STs. HMs are characterized by lower rates of target populations, most having > 25,000 newly diagnosed patients annually (25% vs 78%). Recruitment targets are smaller for AA studies for HMs (median, 82 vs 295 patients) and subpart H studies (median, 295 vs 535). Conclusions: Rates of conversion from AA to RA remain poor for drugs for hematologic malignancies but not for solid tumors drugs. In spite of ODAC meetings and two congressional inquiries, little progress ahs been made towards completing these trials. RADAR continues to urge policy makers to modify the AA process for drugs used to treat hematologic malignancies. Hematologic malignancy drugs receiving AA prior to 2005 and current status of subpart studies Drug AA Indication Pts in AA trial design AA year Target # of pts in Subpart H study RA Year Imatinib mesylate CML 1027 2001 1027 2003 Bortezomib MM 202 2003 669 2005 Denileukin difitox* CTCL** 71 1999 195 Pending Liposomal cytarabine* Lymphomatous meningitis** 33 1999 195 Pending Gemtuzumab ozogamicin* AML** 142 2000 342 Pending Alemtuzumab* B-Cell Chronic lymphocytic leukemia** 93 2001 197 Pending Ibritumomab tiuxetan Certain NHLs ** 230 2002 293 Pending Imatinib mesylate CML (pedatrics)** 39 2003 35 Pending Tositumomab Certain NHLs** 60 2003 N/A Pending Solid tumor cancer drugs receiving AA prior to 2005 and current status of subpart studies Drug AA Indication Pts in AA trial design AA year Target # of pts in Subpart H study RA year * Recommendations for completing trials were made at recent ODAC meetings ** Indications with >25,000 new diagnosis annually Irinotecan Colorectal 304 1996 535 1998 Docetaxel Breast 134 1996 326 1998 Capecitabine Breast 163 1998 511 2001 Temozolomide Brain 162 1999 573 2005 Liposomal Doxorubicin* Ovarian 85 1999 474 2005 Oxaliplatin Colorectal 463 2002 795 2004 Anastrozole Breast 9366 2002 6196 2005 Gefitinib Lung 221 2003 1700 2005 Liposomal Doxorubicin* Kaposi’s sarcoma** 77 1995 250 Pending Amifostine Non-small cell lung** 25 1996 366 Withdrawn Imatinib mesylate GI stromal tumors** 147 2002 946 Pending

A phase I clinical study to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of FN-1501 monotherapy in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3150-TPS3150 ◽  
Author(s):  
Gary Edward Richardson ◽  
Ulka N. Vaishampayan ◽  
Lin Lin ◽  
Viviana Bozon ◽  
Ai-Min Hui ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Safety And Efficacy ◽  
Anaplastic Lymphoma ◽  
Flt3 Mutations ◽  
Expansion Cohort

TPS3150 Background: Receptor tyrosine kinases (RTK), a group of transmembrane proteins, are responsible for growth factor signaling transduction in normal cellular functions. Abnormal RTK functions are associated with human tumorigenesis. FMS-like tyrosine kinase 3 (FLT3) belongs to the type III receptor tyrosine kinase family and plays a well-established role in normal growth and differentiation of hematopoietic precursor cells. FLT3 mutations have been reported to occur in approximately 30% newly diagnosed AML patients. The internal tandem duplications mutation (FLT3/ITD) is the major mutation and correlated with more aggressive progress and poor prognosis. FN-1501 is an inhibitor of various tyrosine kinases such as cyclin-dependent kinase 4/6(CDK4/6), platelet-derived growth factor receptor (PDGFR), KIT protein, anaplastic lymphoma kinase (ALK) and RET protein, particularly potent on FLT3. The preclinical data generated from biochemical, cell based and animal in vivo studies suggest that FN-1501 as a single agent could offer cancer patients clinical benefit by inhibiting multiple tyrosine kinases including FLT3, PDGFR, KIT, ALK, and RET. Methods: This is a Phase1, open label, multicenter, dose-escalation study that will evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of FN-1501 in up to 33 cancer patients with solid tumors. There is a dose escalation phase that will be followed by an expansion cohort. The dose escalation phase utilizes a standard “3 + 3” design where doses of FN-1501 will be escalated up to the Maximum-Tolerated Dose (MTD) or until the Recommended Phase 2 dose (RP2D) is identified. Once the MTD or RP2D dose is identified, an expansion cohort including patients with hematologic malignancies will be enrolled to further evaluate the safety and efficacy of FN-1501. Key exploratory analyses will include an evaluation of safety and efficacy and levels of expression and/or amplification of FLT3 mutations. As of February 8, 2019, cohorts 1 and 2 have been completed without a dose limiting toxicity (DLT). A total of 11 patients have been treated. Enrollment to cohort 3 is on-going. Clinical trial information: NCT03690154.

scholarly journals Therapeutic Potential of Plants as Anti-Microbials for Drug Discovery

2010 ◽  
Vol 7 (3) ◽  
pp. 283-294 ◽  
Author(s):  
Ramar Perumal Samy ◽  
Ponnampalam Gopalakrishnakone
Keyword(s):  
Drug Discovery ◽  
Therapeutic Potential ◽  
Modern Medicine ◽  
Current Status ◽  
Traditional Medicinal Plants ◽  
Recent Trends ◽  
Clinical Trails ◽  
Treatment Of Infection

The uses of traditional medicinal plants for primary health care have steadily increased worldwide in recent years. Scientists are in search of new phytochemicals that could be developed as useful anti-microbials for treatment of infectious diseases. Currently, out of 80% of pharmaceuticals derived from plants, very few are now being used as anti-microbials. Plants are rich in a wide variety of secondary metabolites that have found anti-microbial properties. This review highlights the current status of traditional medicine, its contribution to modern medicine, recent trends in the evaluation of anti-microbials with a special emphasis upon some tribal medicine,in vitroandin vivoexperimental design for screening, and therapeutic efficacy in safety and human clinical trails for commercial outlet. Many of these commercially available compounds are crude preparations administered without performing human clinical trials. Recent methods are useful to standardize the extraction for scientific investigation of new phytochemicals and anti-microbials of traditionally used plants. It is concluded that once the local ethnomedical preparations of traditional sources are scientifically evaluated before dispensing they should replace existing drugs commonly used for the therapeutic treatment of infection. This method should be put into practice for future investigations in the field of ethnopharmacology, phytochemistry, ethnobotany and other biological fields for drug discovery.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

Stem Cell Transplantation: A Promising Therapy for Spinal Cord Injury

2020 ◽  
Vol 15 (4) ◽  
pp. 321-331 ◽  
Author(s):  
Zhe Gong ◽  
Kaishun Xia ◽  
Ankai Xu ◽  
Chao Yu ◽  
Chenggui Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Current Status ◽  
Cord Injury

Spinal Cord Injury (SCI) causes irreversible functional loss of the affected population. The incidence of SCI keeps increasing, resulting in huge burden on the society. The pathogenesis of SCI involves neuron death and exotic reaction, which could impede neuron regeneration. In clinic, the limited regenerative capacity of endogenous cells after SCI is a major problem. Recent studies have demonstrated that a variety of stem cells such as induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and Neural Progenitor Cells (NPCs) /Neural Stem Cells (NSCs) have therapeutic potential for SCI. However, the efficacy and safety of these stem cellbased therapy for SCI remain controversial. In this review, we introduce the pathogenesis of SCI, summarize the current status of the application of these stem cells in SCI repair, and discuss possible mechanisms responsible for functional recovery of SCI after stem cell transplantation. Finally, we highlight several areas for further exploitation of stem cells as a promising regenerative therapy of SCI.

scholarly journals Repurposing existing drugs for new uses: a cohort study of the frequency of FDA-granted new indication exclusivities since 1997

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Babak Sahragardjoonegani ◽  
Reed F. Beall ◽  
Aaron S. Kesselheim ◽  
Aidan Hollis
Keyword(s):  
Therapeutic Potential ◽  
Drug Repurposing ◽  
Status Quo ◽  
New Drugs ◽  
Generic Entry ◽  
Small Molecule Drugs ◽  
Clinical Investigations ◽  
Fda Approval ◽  
Limited Duration ◽  
Observation Period

Abstract Background Drug repurposing (i.e., finding novel uses for existing drugs) is essential for maximizing medicines’ therapeutic utility, but obtaining regulatory approval for new indications is costly. Policymakers have therefore created temporary indication-specific market exclusivities to incentivize drug innovators to run new clinical investigations. The effectiveness of these exclusivities is poorly understood. Objective To determine whether generic entry impacts the probability of new indication additions. Methods For a cohort of all new small-molecule drugs approved by the FDA between July 1997 and May 2020, we tracked new indications added for the subset of drugs that experienced generic entry during the observation period and then analyzed how the probability of a new indication changed with the number of years since/to generic entry. Results Of the 197 new drugs that subsequently experienced generic entry, only 64 (32%) had at least one new indication added. The probability of a new indication addition peaked above 4% between 7 and 8 years prior to generic entry and then to dropped to near zero 15 years after FDA approval. We show that the limited duration of exclusivity reduces the number of secondary indications significantly. Conclusion Status quo for most drug innovators is creating novel one-indication products. Despite indication-specific exclusivities, the imminence of generic entry still has a detectable impact on reducing the chances of new indication additions. There is much room for improvement when it comes to incentivizing clinical investigations for new uses and unlocking existing medicines’ full therapeutic potential.

scholarly journals Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jillian Hattaway Luttman ◽  
Ashley Colemon ◽  
Benjamin Mayro ◽  
Ann Marie Pendergast
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Abl Kinases ◽  
Treatment Paradigm

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

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