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

908

Literatures (Medical) associated with Plicamycin

02 Jun 2025·CANCER RESEARCH

Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma

Article

Author: Morís, Francisco ; Zhao, Yingying ; Xia, Xianyou ; Sun, Shao-Kai ; Huo, Dawei ; Lv, Xuejiao ; Li, Ting ; Yuan, Ye ; Yan, Han ; Jing, Renwei ; Wang, Fan ; Wu, Xudong ; Sun, Yu ; Tong, Yujie ; Liu, Deng ; Tang, Yujie ; Cao, Lei ; Zhao, Qian ; Kong, Yu ; Li, Qian

Abstract:

Diffuse intrinsic pontine gliomas (DIPG) are lethal pediatric brain tumors that frequently harbor H3K27M mutations and lack effective treatments. In this study, our epigenomic analyses uncovered an enrichment of specificity protein/Krüppel-like factor (SP/KLF) transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared with normal pontine neural progenitor cells. SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized mithramycin analog, significantly suppressed the proliferation and invasiveness of H3K27M-DIPG cells. A screen of epigenetic drugs showed that histone deacetylase inhibitors (HDACi) synergized with EC-8042 to suppress H3K27M-DIPG cell growth. Unexpectedly, HDACis activated transcriptional programs that enhanced tumor adaptability and invasiveness, an effect counteracted by EC-8042. Mechanistically, HDACi treatment enhanced chromatin accessibility to SP/KLF factors, whereas EC-8042 disrupted both the primary SP/KLF transcription regulatory network and the HDACi-induced secondary network. Consequently, the combination treatment significantly impeded tumor progression in orthotopic xenograft models. Transcriptomic profiling indicated that this combinatorial strategy induced transcriptional changes associated with improved prognosis in patients with DIPG. Thus, this study identifies a therapeutic approach for H3K27M-mutated DIPGs and sheds light on the limitations of HDACis in treating solid tumors.Significance: The SP/KLF transcriptional regulatory network is activated in H3K27M-mutated diffuse intrinsic pontine glioma and represents a promising therapeutic target in combination with HDAC inhibitors for combating these lethal pediatric brain tumors.

02 Jun 2025·MOLECULAR PHARMACEUTICS

Development and In Vitro Characterization of Milk-Derived Extracellular Vesicle-Mithramycin Formulations for Potential Glioma Therapy

Article

Author: Patnam, Sreekanth ; Thakur, Basant Kumar ; Ali, Mohammad Sadik ; Manda, Sasidhar Venkata ; Singh, Anula Divyash ; Rengan, Aravind Kumar

Glioblastoma (GBM) is a highly aggressive brain tumor with resistance to conventional therapies. Mithramycin (Mit-A), a potent antitumor agent, has shown promise in several tumor types including, GBM. However, its clinical application is limited by toxicity. To address this, we explored the use of milk-derived extracellular vesicles (mEVs) as a delivery system to enhance the therapeutic efficacy of Mit-A. In this study, mEVs were isolated using a 3000 PEG precipitation method and confirmed their size, morphology, and stability through dynamic light scattering (DLS), transmission electron microscopy (TEM), and atomic force microscopy (AFM). The isolated vesicles with a size of 125.6 ± 2.78 nm, a polydispersity index (PDI) of 0.083 ± 0.02, and a ζ-potential of 15 ± 0.57 mV. The presence of typical EV markers such as TSG101, HSP70, and CD63 confirmed their purity. Encapsulation of Mit-A within mEVs led to a slight increase in size to 131.8 ± 6.9 nm, a PDI of 0.081 ± 0.006, and a decrease in ζ-potential to -17 ± 2.0 mV, with an encapsulation efficiency of 58% by the freeze-thaw method. The in vitro transepithelial transport assay revealed that mEV(Mit-A) transported Mit-A more effectively than free Mit-A. The mEV(Mit-A) formulation demonstrated excellent stability in simulated salivary and gastrointestinal fluids, with a sustained release of Mit-A observed over 24 h in vitro in PBS (pH 6.8). Furthermore, mEV(Mit-A) formulations significantly inhibited glioma cell growth, and migration, and induced apoptosis, showing a 2-fold lower IC50 than free Mit-A, indicating superior efficacy. These findings suggest that mEVs represent a promising delivery vehicle for Mit-A, enhancing its potential as an effective treatment for glioblastoma.

01 Jun 2025·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

Inhibition of the Sp1/PI3K/AKT signaling pathway exacerbates doxorubicin-induced cardiomyopathy

Article

Author: Xiao, Huazhen ; Nwaele, Cornelius Obinna ; Liu, Yucheng ; Wang, Qingfeng ; Xiang, Guojian ; Zheng, Yonghong ; Shi, Tingting ; Zhang, Jiancheng

OBJECTIVE:

This study aimed to investigate the interaction and underlying mechanisms between specificity protein 1 (Sp1) and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the context of doxorubicin-induced cardiomyopathy (DIC).

METHODS:

A rat model of DIC was established by intraperitoneal injection of doxorubicin (1 mg/kg) twice a week for eight weeks. Cardiac function was evaluated using echocardiography, and myocardial histopathology was assessed by hematoxylin-eosin (HE) staining. In vitro, H9c2 cardiomyocytes were treated with doxorubicin (2 μmol/L) to induce cardiotoxicity, followed by co-treatment with the Sp1 inhibitor plicamycin or the PI3K/AKT inhibitor LY294002. Cell viability was measured by the CCK-8 assay. Oxidative stress markers, including reactive oxygen species (ROS) and lactate dehydrogenase (LDH), were quantified using flow cytometry and colorimetric assays. Apoptosis was detected via TUNEL staining, and protein expression of Sp1, PI3K, AKT, and Caspase-3 was analyzed by Western blotting.

RESULTS:

Doxorubicin treatment significantly impaired cardiac function in rats, as evidenced by an increase in both left ventricular internal diameters during diastole (LVIDd) and systole (LVIDs), along with decreased ejection fraction (EF) and fractional shortening (FS) (p < 0.01). Myocardial HE staining in doxorubicin-treated rats revealed disorganized cardiomyocyte structures, edema, and cellular necrosis. In vitro, doxorubicin exposure led to reduced H9c2 cell viability, elevated ROS and LDH levels, and increased apoptosis rates (p < 0.01). Western blotting demonstrated that doxorubicin significantly downregulated the expression of Sp1, PI3K, and AKT while upregulating Caspase-3. Inhibition of Sp1 or PI3K/AKT exacerbated these effects, resulting in further cardiac dysfunction, oxidative stress, and apoptosis. Moreover, Sp1 inhibition led to decreased PI3K/AKT pathway activation, while PI3K/AKT inhibition reciprocally suppressed Sp1 expression, indicating a bidirectional regulatory relationship.

CONCLUSION:

Doxorubicin induces cardiotoxicity by promoting oxidative stress and apoptosis through the downregulation of the Sp1/PI3K/AKT signaling pathway. Inhibition of this pathway exacerbates cardiac injury, suggesting that targeting Sp1 and PI3K/AKT may offer novel therapeutic strategies for the prevention and treatment of DIC.

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

Approved

10 top approved records.

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

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ewing Sarcoma	Preclinical	United States	University of North Texas Health Science Center	30 Apr 2025

Clinical Result

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Evaluation

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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)	ggqimuhzso = kqtuzwjphj ehkhkbehah (hamatihhhg, rcqgjkgwfl - lpszliayfj) View more	-	30 Dec 2019
				mithramycin (Dose Level 1 - 30 mcg/kg Extra Thoracic Malignancy)	ggqimuhzso = peayhcsbrw ehkhkbehah (hamatihhhg, psgmmixagt - aidylpyskp) View more
NCT01610570 (CTgov)	Phase 1/2	Solid tumor \| Recurrent Ewing Sarcoma \| Ewing Sarcoma ... View more	8	Mithramycin (Phase I Dose Level -1)	udovfhzdzs(eshbtgdirl) = aroplqqdjo tyckjagcrs (cwvishsxjn, kzkfhycwai - sytyxozxxa) View more	-	15 Feb 2016
				Mithramycin (Phase I Dose Level 1)	vjyvkefhgb = kpxeaedzei bhaqqtlhmy (gkcftypjfi, ajtyrtfutn - tuborvdqpj) View more

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