Phase I/II Evaluation of Continuous 24h Intravenous Infusion of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Primary Thoracic Malignancies or Carcinomas, Sarcomas or Germ Cell Neoplasms With Pleuropulmonary Metastases

Background:
Mithramycin is a new cancer drug. In another study, people with chest cancer took the drug 6 hours a day for 7 straight days. Many of them had liver damage as a side effect. It was discovered that only people with certain genes got this side effect. Researchers want to test mithramycin in people who do not have those certain genes.
Objectives:
To find the highest safe dose of mithramycin that can be given to people with chest cancer who have certain genes over 24 hours instead of spread out over a longer period of time. To see if mithramycin given as a 24-hour infusion shrinks tumors.
Eligibility:
People ages 18 and older who have chest cancer that is not shrinking with known therapies, and whose genes will limit the chance of liver damage from mithramycin
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Lung and heart function tests
X-rays or scans of their tumor
Liver ultrasound
Tumor biopsy
Participants will be admitted to the hospital overnight. A small plastic tube (catheter) will be inserted in the arm or chest. They will get mithramycin through the catheter over about 24 hours.
If they do not have bad side effects or their cancer does not worsen, they can repeat the treatment every 14 days.
Participants will have multiple visits for each treatment cycle. These include repeats of certain screening tests.
After stopping treatment, participants will have weekly visits until they recover from any side effects.

Start Date08 Aug 2019

Sponsor / Collaborator

National Cancer Institute

NCT01624090 / TerminatedPhase 2IIT

Phase II Evaluation of Mithramycin, an Inhibitor of Cancer Stem Cell Signaling, in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum

Background:
- Mithramycin is a drug that was first tested as a cancer therapy in the 1960s. It acted against some forms of cancer, but was never accepted as a treatment. Research suggests that it may be useful against some cancers of the chest, such as lung and esophageal cancer or mesothelioma. Researchers want to see if mithramycin can be used to treat these types of cancer.
Objectives:
- To see if mithramycin is safe and effective against different chest cancers.
Eligibility:
- Individuals at least 18 years of age who have lung, esophagus, pleura, or mediastinum cancers.
Design:
Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor tissue samples will be used to monitor the cancer before treatment.
Participants will receive mithramycin every day for 7 days, followed by 7 days without treatment. Each 14-day round of treatment is called a cycle.
Treatment will be monitored with frequent blood tests and imaging studies.
Participants will continue to take the drug for as long as the side effects are not severe and the tumor responds to treatment.

Start Date06 Sep 2012

Sponsor / Collaborator

National Cancer Institute

NCT01610570 / TerminatedPhase 1/2IIT

Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWSFLI1 Fusion Transcript (Phase II)

Background:
- Mithramycin is a drug that was first tested as a cancer therapy in the 1960s. It acted against some forms of cancer, but was never accepted as a treatment. Research suggests that it may be useful against some solid tumors, particularly Ewing sarcoma. Researchers want to see if mithramycin can be used to treat solid tumors in children and adults. It will be tested in different groups of people, including those with a type of Ewing sarcoma that contains a chemical called Ewings sarcoma - friend leukemia integration 1 transcription factor (EWS-FLI1).
Objectives:
- To see if mithramycin is safe and effective against solid tumors and Ewing sarcoma in children and adults.
Eligibility:
Children and young adults between 1 and 17 years of age with solid tumors that have not responded to standard treatment.
Adults at least 18 years of age with EWS-FLI1 Ewing sarcoma that has not responded to standard treatment.
Children and young adults between 1 and 17 years of age with EWS-FLI1 Ewing sarcoma that has not responded to standard treatment.
Design:
Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor tissue samples will be used to monitor the cancer before treatment. Individuals with solid brain tumors will not be eligible.
Participants will receive mithramycin every day for 7 days, followed by 14 days without treatment. Each 28-day round of treatment is called a cycle.
Treatment will be monitored with frequent blood tests and imaging studies.
Participants will continue to take the drug for as long as the side effects are not severe and the tumor responds to treatment.

Start Date10 May 2012

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Plicamycin

100 Translational Medicine associated with Plicamycin

100 Patents (Medical) associated with Plicamycin

1,175

Literatures (Medical) associated with Plicamycin

23 Jan 2024·Journal of virology

Specificity protein 1 (Sp1) and glucocorticoid receptor (GR) stimulate bovine alphaherpesvirus 1 (BoHV-1) replication and cooperatively transactivate the immediate early transcription unit 1 promoter

Article

Author: Jones, Clinton ; El-Mayet, Fouad S

ABSTRACT:

Bovine alphaherpesvirus 1 (BoHV-1) infections cause respiratory tract disorders and suppress immune responses, which can culminate in bacterial pneumonia. Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons present in trigeminal ganglia (TG) and unknown cells in pharyngeal tonsil. Latently infected calves consistently reactivate from latency after an intravenous injection of the synthetic corticosteroid dexamethasone (DEX), which mimics the effects of stress. The immediate early transcription unit 1 (IEtu1) promoter drives expression of infected cell protein 0 (bICP0) and bICP4, two key viral transcriptional regulators. The IEtu1 promoter contains two functional glucocorticoid receptor (GR) response elements (GREs), and this promoter is transactivated by GR, DEX, and certain Krüppel transcription factors that interact with GC-rich motifs, including consensus specificity protein 1 (Sp1) binding sites. Based on these observations, we hypothesized that Sp1 stimulates productive infection and transactivates key BoHV-1 promoters. DEX treatment of latently infected calves increased the number of Sp1 + TG neurons and cells in pharyngeal tonsil indicating that Sp1 expression is induced by stress. Silencing Sp1 protein expression with siRNA or mithramycin A, a drug that preferentially binds GC-rich DNA, significantly reduced BoHV-1 replication. Moreover, BoHV-1 infection of permissive cells increased Sp1 steady-state protein levels. In transient transfection studies, GR and Sp1 cooperatively transactivate IEtu1 promoter activity unless both GREs are mutated. Co-immunoprecipitation studies revealed that GR and Sp1 interact in mouse neuroblastoma cells (Neuro-2A) suggesting this interaction stimulates IEtu1 promoter activity. Collectively, these studies suggested that the cellular transcription factor Sp1 enhances productive infection and stress-induced BoHV-1 reactivation from latency.

IMPORTANCE:

Following acute infection, bovine alphaherpesvirus 1 (BoHV-1) establishes lifelong latency in sensory neurons in trigeminal ganglia (TG) and pharyngeal tonsil. The synthetic corticosteroid dexamethasone consistently induces BoHV-1 reactivation from latency. The number of TG neurons and cells in pharyngeal tonsil expressing the cellular transcription factor specificity protein 1 (Sp1) protein increases during early stages of dexamethasone-induced reactivation from latency. Silencing Sp1 expression impairs BoHV-1 replication in permissive cells. Interestingly, mithramycin A, a neuroprotective antibiotic that preferentially binds GC-rich DNA, impairs Sp1 functions and reduces BoHV-1 replication suggesting that it is a potential antiviral drug. The glucocorticoid receptor (GR) and Sp1 cooperatively transactivate the BoHV-1 immediate early transcript unit 1 (IEtu1) promoter, which drives expression of infected cell protein 0 (bICP0) and bICP4. Mithramycin A also reduced Sp1- and GR-mediated transactivation of the IEtu1 promoter. These studies revealed that GR and Sp1 trigger viral gene expression and replication following stressful stimuli.

12 Jan 2024·ACS pharmacology & translational science

Differential Expression of SRY-Related HMG-Box Transcription Factor 2, Oligodendrocyte Lineage Transcription Factor 2, and Zinc Finger E-Box Binding Homeobox 1 in Serum-Derived Extracellular Vesicles: Implications for Mithramycin Sensitivity and Targeted Therapy in High-Grade Glioma

Article

Author: Kumar, Dilli ; Kamath, Ajith V. ; Biswas, Manjusha ; Ray, Amitava ; Singh, Anula Divyash ; Manda, Sasidhar Venkata ; Nagalla, Balakrishna ; Rengan, Aravind Kumar ; Majumder, Biswanath ; Patnam, Sreekanth ; Joshi, Parth ; Ranjan, Alok ; Majumder, Pradip K.

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and is often resistant to traditional therapies. Evidence suggests that glioma stem cells (GSCs) contribute to this resistance. Mithramycin (Mit-A) targets GSCs and exhibits antitumor activity in GBM by affecting transcriptional targets such as SRY-related HMG-box transcription factor 2 (SOX2), oligodendrocyte lineage transcription factor 2 (OLIG2), and zinc finger E-box binding homeobox 1 (ZEB1). However, its clinical use has been limited by toxicity. This study explored the diagnostic potential of serum extracellular vesicles (EVs) to identify Mit-A responders. Serum EVs were isolated from 70 glioma patients, and targeted gene expression was analyzed using qRT-PCR. Using chemosensitivity assay, we identified 8 Mit-A responders and 17 nonresponders among 25 glioma patients. The M-score showed a significant correlation (p = 0.045) with isocitrate dehydrogenase 1 mutation but not other clinical variables. The genes SOX2 (p = 0.005), OLIG2 (p = 0.003), and ZEB1 (p = 0.0281) were found to be upregulated in the responder EVs. SOX2 had the highest diagnostic potential (AUC = 0.875), followed by OLIG2 (AUC = 0.772) and ZEB1 (AUC = 0.632).The combined gene panel showed significant diagnostic efficacy (AUC = 0.956) through logistic regression analysis. The gene panel was further validated in the serum EVs of 45 glioma patients. These findings highlight the potential of Mit-A as a targeted therapy for high-grade glioma based on differential gene expression in serum EVs. The gene panel could serve as a diagnostic tool to predict Mit-A sensitivity, offering a promising approach for personalized treatment strategies and emphasizing the role of GSCs in therapeutic resistance.

01 Jan 2024·Pain

Chemotherapy for pain: reversing inflammatory and neuropathic pain with the anticancer agent mithramycin A

Article

Author: Sheehan, Kayla ; Rader, Gabriella ; Xu, Zheyun ; Fujii, Keisuke ; Eilers, Helge ; Lee, Man-Cheung ; Sharma, Manohar ; Kober, Kord ; Varney, Scarlett ; Schumacher, Mark A ; Miaskowski, Christine ; Levine, Jon D ; Rabl, Katalin

Abstract:

The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or reverse persistent pain states. Our prior observations found that Sp1-like transcription factors drive the expression of TRPV1, a pain receptor, that is blocked in vitro by mithramycin A (MTM), an inhibitor of Sp1-like factors. Here, we investigate the ability of MTM to reverse in vivo models of inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) pain and explore MTM's underlying mechanisms. Mithramycin reversed inflammatory heat hyperalgesia induced by complete Freund adjuvant and cisplatin-induced heat and mechanical hypersensitivity. In addition, MTM reversed both short-term and long-term (1 month) oxaliplatin-induced mechanical and cold hypersensitivity, without the rescue of intraepidermal nerve fiber loss. Mithramycin reversed oxaliplatin-induced cold hypersensitivity and oxaliplatin-induced TRPM8 overexpression in dorsal root ganglion (DRG). Evidence across multiple transcriptomic profiling approaches suggest that MTM reverses inflammatory and neuropathic pain through broad transcriptional and alternative splicing regulatory actions. Mithramycin-dependent changes in gene expression following oxaliplatin treatment were largely opposite to and rarely overlapped with changes in gene expression induced by oxaliplatin alone. Notably, RNAseq analysis revealed MTM rescue of oxaliplatin-induced dysregulation of mitochondrial electron transport chain genes that correlated with in vivo reversal of excess reactive oxygen species in DRG neurons. This finding suggests that the mechanism(s) driving persistent pain states such as CIPN are not fixed but are sustained by ongoing modifiable transcription-dependent processes.

News (Medical) associated with Plicamycin

16 Feb 2024

·www.globenewswire.com

OrphAI Therapeutics receives Orphan Drug Designation for AIT-101 as a treatment for amyotrophic lateral sclerosis in the European Union

Feb. 15, 2024 -- OrphAI Therapeutics Inc. (“OrphAI”), a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today that it has received Orphan Drug Designation (ODD) in the European Union (EU) for the treatment of amyotrophic lateral sclerosis (ALS). AIT-101 previously received ODD from the U.S. FDA in June 2023 for the treatment of ALS. “OrphAI Therapeutics now has orphan designation for AIT-101 both in the US and the EU for the treatment of ALS, an important step toward bringing the drug to patients suffering from this neurodegenerative disorder,” said Dr. Brigette Roberts, CEO and Director of OrphAI. “AIT-101 has demonstrated compelling activity in its ability to clear toxic aggregates, which are a hallmark of ALS and other neurodegenerative diseases. We look forward to moving AIT-101 into the next stage of clinical development." AIT-101 is a first-in-class, potent and highly selective inhibitor of the lipid kinase PIKfyve. Inhibition of PIKfyve leads to activation of the transcription factor TFEB which drives the increased clearance of toxic protein aggregates via the lysosomal autophagy pathway. AIT-101 has now been demonstrated to reduce aggregates in human subjects, to improve the survival of motor neurons in in vitro models of familial and sporadic ALS, and to ameliorate functional deficits in a mutant TDP-43 animal model of ALS. AIT-101 is the most clinically advanced PIKfyve inhibitor in development. OrphAI Therapeutics’ mission is to transform the lives of patients with rare diseases. The company is currently developing three investigational therapies across multiple orphan indications: AIT-101, a first-in-class PIKfyve inhibitor, which recently completed a Phase 2a clinical trial in amyotrophic lateral sclerosis (ALS); LAM-001, a proprietary inhaled form of rapamycin, currently in Phase 2 for Group 1 and 3 pulmonary hypertension and bronchiolitis obliterans syndrome (BOS); and AIT-102, a proprietary analogue of mithramycin, in preclinical development, for the treatment of SWI/SNF mutated or dysregulated tumors. The content above comes from the network. if any infringement, please contact us to modify.

Orphan DrugClinical Result

24 Jan 2024

·www.globenewswire.com

OrphAI Therapeutics Announces Appointment of Jay Fine to Board of Directors

Seasoned leader in drug discovery and developmentGUILFORD, Conn., Jan. 24, 2024 (GLOBE NEWSWIRE) -- OrphAI Therapeutics Inc. (“OrphAI”), a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today the appointment of Jay S. Fine, Ph.D. to its Board of Directors. Dr. Fine has a strong track record of drug discovery and development leadership in respiratory diseases, oncology, immunology and fibrotic disease indications. His leadership has contributed to the progression of over 30 new molecular entities into clinical development, leading to the commercial launch of multiple products including Skyrizi™ for Plaque Psoriasis, Psoriatic Arthritis and Crohn’s Disease and Spevigo™ for Generalized Pustular Psoriasis. He has chaired various governance and steering committees at several global pharmaceutical companies. Dr. Fine currently serves as President of Research and Development at EvolveImmune Therapeutics, a development-stage company focused on advancing differentiated immunotherapeutic approaches for the treatment of cancer. Previously, he served as Senior Vice President and Global Therapeutic Area Head for Immunology and Respiratory Diseases Research at Boehringer Ingelheim and as the Discovery Research Site Head at their Ridgefield, CT location. Dr. Fine also served as Head of Translational Biology at Roche Pharmaceuticals, was a Director in the Inflammation department at Schering-Plough and worked in the Biologic Response Modifiers Program at the National Cancer Institute. He holds a B.S. degree from Cornell University and a Ph.D. from the University of Rochester School of Medicine. Dr. Fine has authored over 75 scientific publications and patents and has been the recipient of numerous honors and awards during his career. “Jay Fine represents an extraordinary resource both for the Board as well as for the OrphAI management team, given his years of experience and success in the operational leadership of drug discovery and development. I am personally excited to work with him in this capacity,” said Dr. Brigette Roberts, CEO and Director of OrphAI. “I am very pleased to join the OrphAI Therapeutics’ Board of Directors,” said Dr. Fine. “The company has established an exciting product pipeline which holds tremendous potential to meaningfully improve the lives of patients with rare diseases. I look forward to working closely with the OrphAI team and its board to accelerate the progress of its promising pipeline.” “We are excited to welcome Jay Fine to our Board of Directors,” said David Scheer, Chairman of the Board of Directors at OrphAI. “Jay’s extensive leadership experience and drug development insights will be especially valuable to OrphAI and our Board as we collectively embark on this next stage of the company’s growth.” About OrphAI Therapeutics OrphAI Therapeutics’ mission is to transform the lives of patients with rare diseases. The company is currently developing three investigational therapies across multiple orphan indications: AIT-101, a first-in-class PIKfyve inhibitor, which recently completed a Phase 2a clinical trial in amyotrophic lateral sclerosis (ALS); LAM-001, a proprietary inhaled form of rapamycin, currently in Phase 2 for bronchiolitis obliterans syndrome (BOS) and pulmonary arterial hypertension (PAH); and AIT-102, a proprietary analogue of mithramycin, in preclinical development for the treatment of SWI/SNF mutated or dysregulated tumors. To learn more, please visit: OrphAI-Therapeutics.com

Phase 2Executive Change

02 Oct 2023

·www.biospace.com

OrphAI Therapeutics Announces Oral Presentation and Posters at the 22nd Annual NEALS Conference

GUILFORD, Conn., Oct. 02, 2023 (GLOBE NEWSWIRE) -- OrphAI Therapeutics Inc., a clinical-stage biopharmaceutical company developing novel therapeutics for rare diseases, announced today data presentations at the 22nd Annual NEALS (Northeast ALS Consortium) meeting being held October 4 - 6, 2023 in Clearwater Florida. Oral Presentation: October 5, 2023, 11:10 a.m. ET Title: Results of the Phase 2a clinical trial of LAM-002A (apilimod dimesylate) in C9orf72 ALS Presenters: Dr. Suma Babu, Sean M. Healey Center for ALS at MGHl; Peter Young, Ph.D. Chief Scientific Officer, OrphAI Therapeutics. Location: Opal Ballroom Poster Presentations: Title: AIT-101 Improves Functional Deficits in a Human TDP-43 Animal Model of ALS Presenter: Peter Young, Ph.D., Chief Scientific Officer, OrphAI Therapeutics Location and Time: Poster Session 1, Abstract:4, October 4, 2023, 5:15p – 7:15p ET Title: Results of a double blind, placebo-controlled clinical trial of AIT-101 (LAM-002A) in C9ORF72 ALS- A biomarker driven Phase 2a clinical trial targeting PIKfyve inhibition Presenter: Dr. Suma Babu, Sean M. Healey Center for ALS at MGH Location and Time: Poster Session 2, Abstract:136, October 5, 2023, 4:30p - 6:30p ET About OrphAI Therapeutics OrphAI Therapeutics’ mission is to transform the lives of patients with rare diseases. The company is currently developing three investigational therapies across multiple orphan indications: AIT-101, a first-in-class PIKfyve inhibitor, which recently completed a Phase 2a clinical trial in amyotrophic lateral sclerosis (ALS); LAM-001, a proprietary inhaled form of rapamycin, currently in Phase 2 for bronchiolitis obliterans syndrome (BOS) and pulmonary arterial hypertension (PAH); and AIT-102, a proprietary analogue of mithramycin, in preclinical development for the treatment of SWI/SNF mutated or dysregulated tumors. To learn more, please visit: OrphAI-Therapeutics.com MEDIA CONTACT: info@orphai-therapeutics.com

Phase 2Clinical Result

100 Deals associated with Plicamycin

External Link

KEGG	Wiki	ATC	Drug Bank
D00468	Plicamycin	L01DC02	DB06810

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Hypercalcemia	US	Pfizer Laboratories (Pty) Ltd.	05 May 1970

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01624090 (CTgov)	Phase 2	Lung Cancer \| Esophageal Carcinoma \| Mesothelioma ... View more	16	mithramycin (Dose Level 1 - 30 mcg/kg Thoracic Malignancy)	bpcoaswgvd(jpjaczqpzq) = vnnsiqxyge wyszdwxsbj (elhvapxefi, pkxepilscf - kljtthxpov) View more	-	30 Dec 2019
				mithramycin (Dose Level 1 - 30 mcg/kg Extra Thoracic Malignancy)	bpcoaswgvd(jpjaczqpzq) = pnqysdtxql wyszdwxsbj (elhvapxefi, zaynchsgfr - gvaninbloz) View more
NCT01610570 (CTgov)	Phase 1/2	Solid tumor \| Ewing Sarcoma	8	Mithramycin (Phase I Dose Level -1)	vuakavwdup(ixrlswozoo) = oplvyzraou ocpthxmxeo (mmvtrlcify, tabhtstkia - zwbjpukhro) View more	-	15 Feb 2016
				Mithramycin (Phase I Dose Level 1)	oggimfeqml(xqipriydau) = dzcopyzhzi ziycdqkppq (qyxdcjeqpg, zmcrgvzpxo - hrvxnzrjan) View more

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