scholarly journals The clinical advances of proteolysis targeting chimeras in oncology

Author(s):  
Hao Xie ◽  
Junjia Liu ◽  
Diego M. Alem Glison ◽  
Jason B. Fleming

Proteolysis targeting chimeras (PROTACs) are a class of small molecules designed to target proteins for degradation. Their novel and unique modes of action provide PROTACs with the potential for their application in the management of both solid and hematologic malignancies. Since its initial discovery, the technology of targeted protein degradation, especially in the form of PROTACs, has had significant advances. A number of PROTACs have entered a late stage of preclinical development. Several of them are either in phase 1/2 clinical trials or approaching approval for initial clinical evaluation. This article discusses the preclinical and clinical findings of PROTACs of clinically relevant protein targets in cancer.

Author(s):  
John J. Sramek ◽  
Michael F. Murphy ◽  
Sherilyn Adcock ◽  
Jeffrey G. Stark ◽  
Neal R. Cutler

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound, and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers” , and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights to the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4931-4931
Author(s):  
Mario I. Vega ◽  
Sara Huerta-Yepez ◽  
Melisa Martinez-Paniagua ◽  
Stavroula Baritaki ◽  
Haiming Chen ◽  
...  

Abstract Abstract 4931 Conventional treatments of non-Hodgkin's lymphoma (B-NHL) consist primarily of chemotherapy. Currently, rituximab is used alone or in combination with chemotherapy. However, there are subsets of patients who do not respond initially or develop resistance to further treatment. Therefore, there is an urgent need to develop other immunotherapies with less toxicities. At present, both TRAIL and agonist antibodies directed against TRAIL-R1 and -R2 have been explored for various cancer treatments in various phase 1 and phase 2 clinical trials. We have recently demonstrated that rituximab sensitizes TRAIL-resistant B-NHL cells to TRAIL-induced apoptosis. Sensitization was the result of rituximab-induced inhibition of the constitutively activated NF-κB pathway and downstream the DR5 transcription repressor Yin Yang 1 (YY1). The direct role of YY1 in the regulation of resistance to TRAIL was demonstrated in cells transfected with YY1 siRNA and that became sensitive to TRAIL- apoptosis. Treatment with rituximab did not have any observed effects on the expression of DR4. Based on these findings, it was possible that rituximab-mediated sensitization to TRAIL may invoke either TRAIL-R1 (DR4) or TRAIL-R2 (DR5), or both; thus, this possibility is currently being examined by the use of either neutralizing antibodies against each death receptor or by the use of silencing RNA. Currently, clinical trials are being conducted with both mapatumumab (anti-TRAIL-R1,) and lexatumumab (anti-TRAIL-R2) against a variety of cancers. These agonist antibodies have been evaluated clinically as single agents and in combination with standard therapy in solid and hematologic malignancies. It is not clear whether tumors can develop resistance to agonism of either one or both death receptors and thus, may not respond to monotherapy alone. Combination therapies may be required and we have hypothesized that the combination treatment of rituximab and agonist antibodies may be complementary or synergistic. This hypothesis was based on our findings that rituximab inhibits survival pathways and downregulates anti-apoptotic gene products and, thus, significantly reducing the threshold of resistance. Thus, this rituximab-mediated effect will facilitate the direct cytotoxicity of the agonist death receptor antibodies. The present study investigated whether rituximab can sensitize TRAIL-resistant tumor cells by either agonist TRAIL-R1 or TRAIL-R2 antibodies To address this question, we have examined the effect of agonist antibodies directed against either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumamab). Treatment of the TRAIL-resistant Ramos B-NHL cells with rituximab for 24h and followed with treatment with non-toxic concentrations of mapatumumab (12 μg/ml) or lexatumumab (12 μg/ml) for 18h resulted in significant sensitization to apoptosis as assessed by activation of caspase 3. The mechanism of the sensitization by rituximab for each antibody was also examined. These findings demonstrated that rituximab sensitizes tumor cells to apoptosis by activation of either DR4 or DR5. Although there is heterogeneous expression of TRAIL-R1 and TRAIL-R2 in B-NHL cells, such cells may still be sensitive to rituximab-mediated sensitization to apoptosis by the corresponding agonist death receptor antibody. Recent findings demonstrated that some tumors expressing both DR4 and DR5 were shown to respond to TRAIL by preferential activation of DR4 and not DR5. Therefore, preclinical findings obtained with the use of TRAIL may not be predictive of outcome compared to the use of TRAIL-receptor specific agonist antibodies; mapatumumab or lexatumumab. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5819-5819
Author(s):  
Jordon Jaggers ◽  
Heidi D. Klepin ◽  
Tanya M. Wildes ◽  
Rebecca L. Olin ◽  
Andrew S. Artz ◽  
...  

Introduction: Clinical trial development and enrollment are pivotal to advancing cancer outcomes. Novel treatment modalities such as Chimeric Antigen Receptor (CAR) T-cell therapy is an intensive therapy that has altered the landscape of hematologic malignancy therapies, with several FDA approvals based on Phase I-II studies. Strict eligibility criteria are implemented to ensure safety of trial participants; however, these criteria can lead to barriers to patient enrollment, hinder the generalizability of the study, and result in a population of participants not representative of those who would benefit from therapy. The aim of this proposal is to characterize inclusion and exclusion criteria in clinical trials for CAR-T cellular therapy in adults with hematologic malignancies. Methods: The U.S. National Library of Medicine's Clinical Trial database of privately and publicly funded clinical studies was accessed June 2019 to assemble a list of studies with the following filters applied: hematologic, recruiting, not yet recruiting, not recruiting, active, completed, suspended, terminated studies, interventional studies, CAR, CAR T, chimeric antigen receptor, CAR NK, adult, older adult, early phase 1, phase 1, phase 2, phase 3. From this, 95 studies populated, 84 were utilized in this study and 11 studies excluded due to non-hematologic malignancy. Results: We analyzed 84 CAR-T clinical trials targeting multiple diseases (Table 1) including; acute lymphoblastic (n=7) and myeloid leukemia (n=2); lymphoma (n=6); multiple myeloma (n=40); multiple hematologic malignancies (n=27) and other (n=2). The majority of studies were phase 1 (n=47) or phase 1/2 (n=28). Upper age limit restrictions were in place for 53/84 (63%) of trials. Trials included the AYA population (n=5), ≤ age 65 (n=1), ≤ age 70 or 73 (n=26), ≤ age 75 or 78 (n=12), ≤ age 80 or 85 (n=9). Of the 84 trials, 65 (77%) had performance status inclusion criteria, most commonly was status ECOG 0-2 (n=23) and ECOG 0-1 (n=24). Patients were excluded for a history of a separate or concurrent malignancy in 52/84 (62%) trials, CNS disease was excluded in 45/84 (54%) trials and 70/84 (83%) clinical trials excluded infectious diseases; HIV (n=69) and Hepatitis B/C (n=64). Many studies had restrictions for impairment in organ function; renal impairment (n=66), cardiac deficits (n=67), and abnormal pulmonary function (n=44). Unique to CAR-T trials, 27/84 had restrictions in place for neurological disorders: epilepsy (n=15), history of brain injury (n=10), dementia (n=8), coordination/movement disorder (n=6), cerebellar disease (n=8), psychosis (n=7), paresis (n=6), history of stroke/aphasia (n=21), and active autoimmune or inflammatory disease of the central nervous system (n=3). Conclusion: CAR-T cellular therapy is a tremendous therapeutic advancement in the medical community. This study emphasizes, in detail, highly variable cross-study inclusion/exclusion criteria for early phase CAR-T studies. This new and promising therapy is actively being studied in a highly select group of patients and may not be generalizable to the older adult with hematologic malignancies due to non-uniform trial criteria. The applicability of this modality should be tempered by the understanding that CAR-T trials have overt age caps, ambiguous performance and comorbidity exclusions, and neurologic exclusions and play a role in limiting patient accessibility to novel clinical trial therapy. Confirmatory prospective and observational studies of CAR-T therapy in representative populations are a high priority. 1. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. 2016 127:3321-3330. Doi: 10.1182/blood-2016-04-703751 2. Kim ES, Bruinooge SS, Roberts S, et al. Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol. 2017;35(33):3737-3744. doi:10.1200/JCO.2017.73.7916 3. Unger JM, Cook E, Tai E, and Bleyer A. The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies. American Society of Clinical Oncology Educational Book. 2016; 36:185-198. Doi:10.1200/EDBK\_156686 Disclosures Wildes: Janssen: Research Funding; Carevive: Consultancy. Olin:Spectrum: Research Funding; Novartis: Research Funding. Artz:Miltenyi: Research Funding. Jaglowski:Unum Therapeutics Inc.: Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Rosko:Vyxeos: Other: Travel support.


2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?


2019 ◽  
Vol 26 (30) ◽  
pp. 5609-5624
Author(s):  
Dijana Saftić ◽  
Željka Ban ◽  
Josipa Matić ◽  
Lidija-Marija Tumirv ◽  
Ivo Piantanida

: Among the most intensively studied classes of small molecules (molecular weight < 650) in biomedical research are small molecules that non-covalently bind to DNA/RNA, and another intensively studied class is nucleobase derivatives. Both classes have been intensively elaborated in many books and reviews. However, conjugates consisting of DNA/RNA binder covalently linked to nucleobase are much less studied and have not been reviewed in the last two decades. Therefore, this review summarized reports on the design of classical DNA/RNA binder – nucleobase conjugates, as well as data about their interactions with various DNA or RNA targets, and even in some cases protein targets are involved. According to these data, the most important structural aspects of selective or even specific recognition between small molecule and target are proposed, and where possible related biochemical and biomedical aspects were discussed. The general conclusion is that this, rather new class of molecules showed an amazing set of recognition tools for numerous DNA or RNA targets in the last two decades, as well as few intriguing in vitro and in vivo selectivities. Several lead research lines show promising advancements toward either novel, highly selective markers or bioactive, potentially druggable molecules.


2020 ◽  
Vol 20 (19) ◽  
pp. 2019-2035
Author(s):  
Esmaeil Sheikh Ahmadi ◽  
Amir Tajbakhsh ◽  
Milad Iranshahy ◽  
Javad Asili ◽  
Nadine Kretschmer ◽  
...  

Naturally occurring naphthoquinones (NQs) comprising highly reactive small molecules are the subject of increasing attention due to their promising biological activities such as antioxidant, antimicrobial, apoptosis-inducing activities, and especially anticancer activity. Lapachol, lapachone, and napabucasin belong to the NQs and are in phase II clinical trials for the treatment of many cancers. This review aims to provide a comprehensive and updated overview on the biological activities of several new NQs isolated from different species of plants reported from January 2013 to January 2020, their potential therapeutic applications and their clinical significance.


2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.


Author(s):  
Alexia Iasonos ◽  
John O’Quigley
Keyword(s):  

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