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BioRxiv : the Preprint Server For... Mar 2023Cas9 is a programmable nuclease that has furnished transformative technologies, including base editors and transcription modulators (e.g., CRISPRi/a), but several...
Cas9 is a programmable nuclease that has furnished transformative technologies, including base editors and transcription modulators (e.g., CRISPRi/a), but several applications of these technologies, including therapeutics, mandatorily require precision control of their half-life. For example, such control can help avert any potential immunological and adverse events in clinical trials. Current genome editing technologies to control the half-life of Cas9 are slow, have lower activity, involve fusion of large response elements (> 230 amino acids), utilize expensive controllers with poor pharmacological attributes, and cannot be implemented on several CRISPR-based technologies. We report a general platform for half-life control using the molecular glue, pomalidomide, that binds to a ubiquitin ligase complex and a response-element bearing CRISPR-based technology, thereby causing the latter's rapid ubiquitination and degradation. Using pomalidomide, we were able to control the half-life of large CRISPR-based technologies (e.g., base editors, CRISPRi) and small anti-CRISPRs that inhibit such technologies, allowing us to build the first examples of on-switch for base editors. The ability to switch on, fine-tune and switch-off CRISPR-based technologies with pomalidomide allowed complete control over their activity, specificity, and genome editing outcome. Importantly, the miniature size of the response element and favorable pharmacological attributes of the drug pomalidomide allowed control of activity of base editor using AAV as the delivery vehicle. These studies provide methods and reagents to precisely control the dosage and half-life of CRISPR-based technologies, propelling their therapeutic development.
PubMed: 36945568
DOI: 10.1101/2023.03.12.531757 -
Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy.Journal of Medicinal Chemistry Jun 2023Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans....
Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans. Heterobivalent BTK protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the BTK inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and characterization of BTK PROTACs based on the selective BTK inhibitor and the cereblon recruitment ligand pomalidomide. is a highly potent BTK degrader (DC 0.5 nM) that inhibited cell growth and induced apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Cell Proliferation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteolysis Targeting Chimera
PubMed: 37195170
DOI: 10.1021/acs.jmedchem.3c00176 -
American Society of Clinical Oncology... 2015Recent developments in the treatment of multiple myeloma (MM) have led to improvements in response rates and to increased survival. A major advance in the last decade... (Review)
Review
Recent developments in the treatment of multiple myeloma (MM) have led to improvements in response rates and to increased survival. A major advance in the last decade has been the introduction of the novel agents thalidomide, bortezomib, and lenalidomide as part of front-line treatment in both the transplant and nontransplant settings. However, disease relapse is inevitable for the majority of patients and myeloma typically recurs more aggressively with each relapse, eventually leading to the development of treatment-refractory disease. Several phase II and III trials have demonstrated the efficacy of recently approved agents in the setting of relapsed and relapsed and refractory MM, including pomalidomide and carfilzomib. Ixazomib, an oral proteasome inhibitor, and multiple other novel classes of agents are being investigated. These include monoclonal antibodies and histone deacetylase inhibitors, which may further add to the therapeutic armamentarium for this malignancy. Therefore, in a disease characterized by multiple relapses, the optimal sequencing of the different effective options is an important consideration in attempting to prolong survival.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Resistance, Neoplasm; Humans; Methotrexate; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Randomized Controlled Trials as Topic; Salvage Therapy; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous; Vincristine
PubMed: 25993216
DOI: 10.14694/EdBook_AM.2015.35.e504 -
European Journal of Haematology Jan 2022We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse.
METHODS
OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS).
RESULTS
Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports.
CONCLUSIONS
These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Female; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Prognosis; Recurrence; Retreatment; Thalidomide; Treatment Outcome
PubMed: 34496096
DOI: 10.1111/ejh.13706 -
Annals of Oncology : Official Journal... Nov 2015While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of... (Review)
Review
While survival times have increased over the last decade, most patients with multiple myeloma (MM) eventually relapse and become refractory to therapy. The treatment of patients with relapsed and/or refractory MM is frequently further complicated by the presence of pre-existing comorbidities that arise from an advanced disease state and of toxicities stemming from prior antimyeloma treatment. Carfilzomib and pomalidomide have recently been approved for the treatment of patients with relapsed and refractory MM. While these agents represent important additions to the available treatment options, the identification of patients who may best benefit from the use of each of therapy is still being investigated. A number of patient-related and disease-related factors may impact treatment efficacy and/or tolerability, and the clinical presentation and medical history of each patient must be carefully considered to optimize treatment. Here, we review results from carfilzomib and pomalidomide clinical trials in patients with relapsed and/or refractory MM who also have baseline comorbidities or treatment-induced or disease-induced complications (including the presence of renal impairment, cardiac risk factors, peripheral neuropathy, or high-risk chromosomal abnormalities) to evaluate the safety and efficacy of the two agents in these difficult-to-treat patients and to provide treatment recommendations specific to each scenario.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials as Topic; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Risk Factors; Thalidomide
PubMed: 26216385
DOI: 10.1093/annonc/mdv325 -
Haematologica Apr 2016The approach to the patient with relapsed or relapsed/refractory multiple myeloma (RRMM) requires a careful evaluation of the results of previous treatments, the... (Review)
Review
The approach to the patient with relapsed or relapsed/refractory multiple myeloma (RRMM) requires a careful evaluation of the results of previous treatments, the toxicities associated with them and an assessment of prognostic factors. Since the majority of patients will have received prior therapy with drug combinations including a proteasome inhibitor and/or an immunomodulatory drug (IMiD), it is the physician's task to choose the right moment for the start of therapy and define with the patient which goals need to be achieved. The choice of regimen is usually based on prior responsiveness, drugs already received, prior adverse effects, the condition of the patient and expected effectiveness and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs like pomalidomide, carfilzomib and monoclonal antibodies are, or will be, available shortly, while other options can be tried in clinical studies. Finally, supportive care and palliative options need to be considered in some patients. It is becoming increasingly more important to consider the therapeutic options for the whole duration of the disease rather than take a step by step approach, and to develop a systematic approach for each individual patient.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Immunologic Factors; Multiple Myeloma; Oligopeptides; Palliative Care; Plasma Cells; Precision Medicine; Proteasome Inhibitors; Recurrence; Thalidomide
PubMed: 27033237
DOI: 10.3324/haematol.2015.129189 -
Haematologica Feb 2024The primary and pre-specified updated analyses of ICARIA-MM (NCT02990338) demonstrated improved progression-free survival and a benefit in overall survival (OS) was...
The primary and pre-specified updated analyses of ICARIA-MM (NCT02990338) demonstrated improved progression-free survival and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase 3 study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide- dexamethasone (Isa-Pd; n = 154) or Pd (n = 153), stratified based on age (3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS (95% confidence interval) was 24.6 months (20.3-31.3 months) with Isa-Pd and 17.7 months (14.4-26.2 months) with Pd (hazard ratio = 0.78; 95% CI, 0.59-1.02; 1-sided P = 0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd vs. Pd (17.5 vs. 12.9 months; log-rank 1-sided P = 0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median overall survival in patients with relapsed/refractory multiple myeloma.
PubMed: 38299578
DOI: 10.3324/haematol.2023.284325 -
OncoTargets and Therapy 2017Small-cell lung cancer (SCLC), a poorly differentiated neuroendocrine malignancy, has a rapid growth rate, strong aggressiveness, early metastases, and poor prognosis.... (Review)
Review
Small-cell lung cancer (SCLC), a poorly differentiated neuroendocrine malignancy, has a rapid growth rate, strong aggressiveness, early metastases, and poor prognosis. Angiogenesis greatly contributes to the metastatic process of SCLC, which has a higher vascularization compared with non-small-cell lung cancer (NSCLC). SCLC might constitute an ideal malignancy for assessing new antiangiogenic drugs and therapeutic strategies. Combining bevacizumab with paclitaxel has therapeutic benefits in chemoresistant, relapsed SCLC. The cisplatin-etoposide and bevacizumab combination, as the first-line treatment for extensive-stage SCLC, can improve progression-free survival (PFS), with an acceptable toxicity profile. Ziv-aflibercept combined with topotecan is promising for platinum-refractory SCLC. Chemotherapy combined with thalidomide cannot prolong survival. Maintenance sunitinib of 37.5 mg/day in extensive-stage SCLC patients following induction chemotherapy with platinum/etoposide improves median PFS by 1.6 months. Serum angiopoietin-2 concentrations and vascular endothelial growth factor levels correlate with poor prognosis. Bevacizumab, ziv-aflibercept, and sunitinib are worthy of further evaluation. Thalidomide, sorafenib, pomalidomide, and cediranib may not be suitable for SCLC.
PubMed: 28138259
DOI: 10.2147/OTT.S119714 -
Blood Sep 2017At present, multiple classes of agents with distinct mechanisms of action are available for the treatment of patients with multiple myeloma (MM), including alkylators,... (Review)
Review
At present, multiple classes of agents with distinct mechanisms of action are available for the treatment of patients with multiple myeloma (MM), including alkylators, steroids, immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), histone deacetylase inhibitors (DACIs), and monoclonal antibodies (mAbs). Over the last 5 years, several new agents, such as the third-generation IMiD pomalidomide, the second-generation PIs carfilzomib and ixazomib, the DACI panobinostat, and 2 mAbs, elotuzumab and daratumumab, have been approved, incorporated into clinical guidelines, and have transformed our approach to the treatment of patients. These agents may be part of doublet or triplet combinations, or incorporated into intensive strategies with autologous stem cell transplantation. In this review, I discuss the different treatment options available today for the treatment of MM in frontline and relapse settings.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma; Therapeutics
PubMed: 28747306
DOI: 10.1182/blood-2017-05-743203 -
Medicine Jan 2023Pomalidomide is an immunomodulatory imide drug used in multiple myeloma and in Kaposi sarcoma.
RATIONALE
Pomalidomide is an immunomodulatory imide drug used in multiple myeloma and in Kaposi sarcoma.
PATIENT CONCERNS
A 72-years-old male, treated for multiple myeloma with dexamethasone, pomalidomide and daratumumab, presented dyspnea, hypoxemia, biological inflammatory syndrome, ground glass opacities on computed tomography scan (CT-scan) and lymphocytic and eosinophilic alveolitis, with no specific cytologic or microbiological findings, 2 months after pomalidomide initiation.
INTERVENTION AND OUTCOME
Antibiotics were started after bronchoscopy. No improvement was noted in dyspnea and biological inflammatory syndrome after 5 days of treatment. Pomalidomide was then discontinued, with continuation of Daratumumab-Dexamethasone, resulting in a rapid recovery of symptoms and CT-scan anomalies. No recurrence of dyspnea was observed during the 15 months of follow-up.
DIAGNOSES
Pomalidomide-induced lung injury.
LESSONS
Pomalidomide-induced lung injury is a rare and serious adverse event that can occur early after Pomalidomide introduction. As pomalidomide use is increasing, the identification of drug toxicity as a possible cause of lung injury appears important. We report a rapid recovery of symptoms and CT-scan anomalies after pomalidomide discontinuation.
Topics: Male; Humans; Aged; Multiple Myeloma; Lung Injury; Dexamethasone; Dyspnea; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36637962
DOI: 10.1097/MD.0000000000032473