scholarly journals The Michael J. Fox Foundation’s Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1878
Author(s):  
Shalini Padmanabhan ◽  
Brian K. Fiske ◽  
Marco A.S. Baptista
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Parkinson Disease ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Critical Research ◽  
Development Activity ◽  
Potential Safety ◽  
Lrrk2 Kinase ◽  
Holistic Description

Since 2005, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has invested significant funding and non-funding effort to accelerate research and drug development activity around the Parkinson disease (PD)-associated protein LRRK2. MJFF has spearheaded multiple public/private pre-competitive collaborations that have contributed to our understanding of LRRK2 function; de-risked potential safety questions around the therapeutic use of LRRK2 kinase inhibitors; and generated critical research tools, biosamples, and data for the field. Several LRRK2-targeted therapies are now in human testing due to the hard work of so many in the PD community. In this perspective, we present a holistic description and model of how our Foundation’s support targeted important barriers to LRRK2 research and helped move the field into clinical trials.

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

scholarly journals Cancer drug development: The missing links

2019 ◽  
Vol 244 (8) ◽  
pp. 663-689 ◽  
Author(s):  
Ajaikumar B Kunnumakkara ◽  
Devivasha Bordoloi ◽  
Bethsebie Lalduhsaki Sailo ◽  
Nand Kishor Roy ◽  
Krishan Kumar Thakur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Drug Development ◽  
Targeted Therapies ◽  
Science And Technology ◽  
Development Cost ◽  
Phase I Clinical Trials ◽  
Drug Benefits ◽  
Number Of Patients ◽  
Pharmaceutical Industries

Although better science and technology has been linked with better health care, however, reality is much different. Although America and most of Europe are equipped with most advanced science and technology, paradoxically cancer incidence is highest in the world. This indicates that science and technology alone is not sufficient in treating diseases like cancer. It is also now well recognized that more than 95% of the drugs/compounds that kill either cancer cells in culture or regress the tumors in animals, fail in phase I clinical trials in humans, indicating that most pre-clinical models of cancer are inadequate. In addition, most of the anticancer drugs that are approved by the regulatory agencies such as FDA either has no effect on the overall survival of the cancer patient or may provide an increase in few months in overall survival. This is despite the fact that most targeted therapies that are currently available are highly expensive; thus suggesting the lack of affordability. This review is meant to focus on some of these problems in detail and then provide potential solutions since most cancers are caused by multiple genes, and thus multi-targeted therapies are needed such as natural products which are inexpensive, safe and have been used for thousands of years for both prevention and treatment of cancer. Impact statement The success rate for cancer drugs which enter into phase 1 clinical trials is utterly less. Why the vast majority of drugs fail is not understood but suggests that pre-clinical studies are not adequate for human diseases. In 1975, as per the Tufts Center for the Study of Drug Development, pharmaceutical industries expended 100 million dollars for research and development of the average FDA approved drug. By 2005, this figure had more than quadrupled, to $1.3 billion. In order to recover their high and risky investment cost, pharmaceutical companies charge more for their products. However, there exists no correlation between drug development cost and actual sale of the drug. This high drug development cost could be due to the reason that all patients might not respond to the drug. Hence, a given drug has to be tested in large number of patients to show drug benefits and obtain significant results.

scholarly journals Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 321 ◽  
Author(s):  
Sobhani ◽  
D’Angelo ◽  
Pittacolo ◽  
Roviello ◽  
Miccoli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Her2 Positive ◽  
Retinoblastoma Tumor

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in recent decades, improving the life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the Cyclin dependent kinase inhibitors family INK4 that specifically inhibit CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years, the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in other BC subtypes. In HER2-positive BC, a combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, the efficacy of CDK4/6 inhibitors has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions for ongoing clinical trials and predictive biomarkers will be further debated.

scholarly journals Mapping the Global Research and Clinical Trials in COVID-19

2020 ◽  
Author(s):  
Ranjana Aggarwal ◽  
Sujit Bhattacharya ◽  
Shubham Singh
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Value Chain ◽  
Academic Research ◽  
Current Status ◽  
Innovation Activity ◽  
Research Papers ◽  
Private Funding ◽  
Development Activity ◽  
Research And Innovation

AbstractCOVID-19 has created an unprecedented level of research and innovation activity globally to bring out drug to control or cure the disease, and develop vaccine for long time prevention. A ‘new/better normal’ is emerging that is trying to push this time period for drug development and vaccine within a year and earlier than that from typical 8 to 10 years for drugs and 10 to 15 years for vaccine. This is happening due to multiple factors: strong policy push by different government that includes dedicated investment, speeding up regulation process, multiple agencies involvement, and multilateral bodies led by WHO trying to create a global platform, huge grants from private funding bodies, strategic linkages across the whole research and innovation value chain between firms, academic, research organisations and start-ups.The paper maps the research papers and ongoing clinical trials to provide an informed view of the current status of the research and drug development activity as seen through the lens of research papers and clinical trials. The intended goal of this study is to help the research community and policy makers to keep track of highly relevant research and drug development in COVID-19.

scholarly journals Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science

2020 ◽  
Vol 4 (1) ◽  
pp. 28-49
Author(s):  
Diane Stephenson ◽  
Robert Alexander ◽  
Varun Aggarwal ◽  
Reham Badawy ◽  
Lisa Bain ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Parkinson Disease ◽  
Critical Path ◽  
Digital Health ◽  
Clinical Manifestations ◽  
Signs And Symptoms ◽  
Sensor Data ◽  
Regulatory Agencies ◽  
Health Technologies

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson’s Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies.

Non-BRAF targeted therapies for melanoma: protein kinase inhibitors in Phase II clinical trials

2014 ◽  
Vol 23 (4) ◽  
pp. 489-500 ◽  
Author(s):  
Shilpa Bhatia ◽  
Luni Emdad ◽  
Swadesh K Das ◽  
Hossein Hamed ◽  
Paul Dent ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Protein Kinase ◽  
Phase Ii ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Phase Ii Clinical Trials

Clinical trial risk reduction in non-small cell lung cancer though the use of biomarkers and receptor-targeted therapies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8040-8040
Author(s):  
Adam Falconi ◽  
Gilberto Lopes ◽  
Jayson L. Parker
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Success Rate ◽  
Targeted Therapies ◽  
Phase Iii ◽  
Clinical Testing ◽  
Phase Ii Trials ◽  
Phase Iii Trials

8040 Background: We analyzed the risk of clinical trial failure duringnon-small cell lung cancer (NSCLC) drug development between 1998 and 2012. Methods: NSCLC drug development was investigated using trial disclosures from publically available resources. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use treatment relevant endpoints. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD). Results: 2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than the expected industry aggregate rates (16.5%). The success of phase III trials was found to be the biggest obstacle for drug approval with a success rate of only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development was calculated to be 1.89 billion US dollars. Use of biomarkers decreased drug development cost by 26% to 1.4 billion US dollars. Potential savings may be even higher if fewer clinical trials are required for successful development. Conclusions: Physicians that enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.

scholarly journals Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
C. P. Gonzalez-Hunt ◽  
E. A. Thacker ◽  
C. M. Toste ◽  
S. Boularand ◽  
S. Deprets ◽  
...  
Keyword(s):  
Dna Damage ◽  
Clinical Trials ◽  
Mitochondrial Dna ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Mtdna Damage ◽  
Mitochondrial Dna Damage ◽  
Lrrk2 G2019s ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Abstract Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson’s disease (PD) and LRRK2 kinase inhibitors are currently being tested in early phase clinical trials. In order to ensure the highest chance of success, a biomarker-guided entry into clinical trials is key. LRRK2 phosphorylation, and phosphorylation of the LRRK2 substrate Rab10, have been proposed as target engagement biomarkers for LRRK2 kinase inhibition. However, a pharmacodynamic biomarker to demonstrate that a biological response has occurred is lacking. We previously discovered that the LRRK2 G2019S mutation causes mitochondrial DNA (mtDNA) damage and is LRRK2 kinase activity-dependent. Here, we have explored the possibility that measurement of mtDNA damage is a “surrogate” for LRRK2 kinase activity and consequently of kinase inhibitor activity. Mitochondrial DNA damage was robustly increased in PD patient-derived immune cells with LRRK2 G2019S mutations as compared with controls. Following treatment with multiple classes of LRRK2 kinase inhibitors, a full reversal of mtDNA damage to healthy control levels was observed and correlated with measures of LRRK2 dephosphorylation. Taken together, assessment of mtDNA damage levels may be a sensitive measure of altered kinase activity and provide an extended profile of LRRK2 kinase modulation in clinical studies.

scholarly journals 10 years into the resurgence of covalent drugs

2020 ◽  
Author(s):  
Elena De Vita
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Drug Development ◽  
Precision Medicine ◽  
Kinase Inhibitors ◽  
Covalent Inhibition ◽  
The Future ◽  
Covalent Inhibitors ◽  
Effective Treatments

In the first decade of targeted covalent inhibition, scientists have successfully reversed the previous trend that had impeded the use of covalent inhibition in drug development. Successes in the clinic, mainly in the field of kinase inhibitors, are existing proof that safe covalent inhibitors can be designed and employed to develop effective treatments. The case of KRASG12C covalent inhibitors entering clinical trials in 2019 has been among the hottest topics discussed in drug discovery, raising expectations for the future of the field. In this perspective, an overview of the milestones hit with targeted covalent inhibitors, as well as the promise and the needs of current research, are presented. While recent results have confirmed the potential that was foreseen, many questions remain unexplored in this branch of precision medicine.

Sign in / Sign up

Export Citation Format

Share Document