Breast intraductal nanoformulations for treating ductal carcinoma in situ II: Dose de-escalation using a slow releasing/slow bioconverting prodrug strategy

Al-Zubaydi, Firas; Gao, Dayuan; Kakkar, Dipti; Li, Shike; Holloway, Jennifer; Székely, Zoltán; Chan, Nancy; Kumar, Shicha; Sabaawy, Hatem E.; Love, Susan M.; Sinko, Patrick J.

doi:10.1007/s13346-021-00903-y

Cited by 6 publications

(6 citation statements)

References 62 publications

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“…CPX itself in fact represents a multitarget approach, as it impacts multiple signaling pathways besides DOHH/eIF5A, such as ribonucleotide reductase, Myc, Wnt/β‐catenin, VEGFR‐3/ERK1/2 and ATR/Chk1/Cdc25A 33 . CPX prodrugs aiming to improve the bioavailability and solubility of CPX are currently being developed by several research groups 34,35 . Moreover, several studies have indicated the therapeutic potential of targeting eif5a pathway in combination with additional therapeutic agents inhibiting other cellular and immune pathways such as imatinib, 36 ROS scavenger, N ‐acetyl‐cysteine (NAC), TOP2A siRNA, 37 IFNα and DSH inhibitors 38 .…”

Section: Resultsmentioning

confidence: 99%

Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short‐term vs long‐term survivors of glioblastoma

Ofek

Yeini

Arad

et al. 2023

Intl Journal of Cancer

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Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the time of diagnosis (ie, long-term survivors [LTS]). In our study, we aimed to identify molecular markers associated with favorable GB prognosis as a basis to develop therapeutic applications to improve patients' outcome. We have recently assembled a proteogenomic dataset of 87 GB clinical samples of varying survival rates. Following RNA-seq and mass spectrometry (MS)-based proteomics analysis, we identified several differentially expressed genes and proteins, including some known cancer-related pathways and some less established that showed higher expression in short-term (<6 months) survivors (STS) compared to LTS. One such target found was deoxyhypusine hydroxylase (DOHH), which is known to be involved in the biosynthesis of hypusine, an unusual amino acid essential for the function of the eukaryotic translation initiation factor 5A (eIF5A), which promotes tumor growth. We consequently validated DOHH overexpression in STS samples by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. We further showed robust inhibition of

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Section: Resultsmentioning

confidence: 99%

Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short‐term vs long‐term survivors of glioblastoma

Ofek

Yeini

Arad

et al. 2023

Intl Journal of Cancer

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“…We and others have shown that i.duc therapy provides a noninvasive modality to treat DCIS at the site of origin. Several types of antitumor agents, including hormone therapy, chemotherapy, and radiotherapy have been investigated in preclinical research ( 21 , 22 , 24 – 28 ), and a safety and feasibility clinical trial was successfully conducted with Doxil administered by the i.duc route ( 22 ). The results are promising overall, but problems still exist, such as suboptimal antitumor efficiency of endocrine agents ( 26 ) and long-term effects of DNA-damaging agents such as chemotherapy and radiotherapy ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

“…That i.duc therapy shows promise for treating DCIS has been demonstrated in several preclinical studies ( 21 – 28 ). As shown by our group, the superior effects of the i.duc route, compared to the systemic route, for the delivery of chemotherapy ( 21 , 22 ), radioactive compounds ( 24 ), and hormonal agents ( 18 , 21 ) stems from the ability to confine the anticancer effects of the agent to the tumor site in the duct while sparing the remainder of the body from its toxic effects.…”

mentioning

confidence: 92%

Intraductal administration of transferrin receptor-targeted immunotoxin clears ductal carcinoma in situ in mouse models of breast cancer—a preclinical study

Wang

Kumar

Ding

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The human transferrin receptor (TFR) is overexpressed in most breast cancers, including preneoplastic ductal carcinoma in situ (DCIS). HB21(Fv)-PE40 is a single-chain immunotoxin (IT) engineered by fusing the variable region of a monoclonal antibody (HB21) against a TFR with a 40 kDa fragment of Pseudomonas exotoxin (PE). In humans, the administration of other TFR-targeted immunotoxins intrathecally led to inflammation and vascular leakage. We proposed that for treatment of DCIS, intraductal (i.duc) injection of HB21(Fv)-PE40 could avoid systemic toxicity while retaining its potent antitumor effects on visible and occult tumors in the entire ductal tree. Pharmacokinetic studies in mice showed that, in contrast to intravenous injection, IT was undetectable by enzyme-linked immunosorbent assay in blood following i.duc injection of up to 3.0 μg HB21(Fv)-PE40. We demonstrated the antitumor efficacy of HB21(Fv)-PE40 in two mammary-in-duct (MIND) models, MCF7 and SUM225, grown in NOD/SCID/gamma mice. Tumors were undetectable by In Vivo Imaging System (IVIS) imaging in intraductally treated mice within 1 wk of initiation of the regimen (IT once weekly/3 wk, 1.5 μg/teat). MCF7 tumor–bearing mice remained tumor free for up to 60 d of observation with i.duc IT, whereas the HB21 antibody alone or intraperitoneal IT treatment had minimal/no antitumor effects. These and similar findings in the SUM225 MIND model were substantiated by analysis of mammary gland whole mounts, histology, and immunohistochemistry for the proteins Ki67, CD31, CD71 (TFR), and Ku80. This study provides a strong preclinical foundation for conducting feasibility and safety trials in patients with stage 0 breast cancer.

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“…beim Morbus Paget der Mamille vom extramammären Typ eine therapeutische Option darstellen kann. Dies belegen auch tierexperimentelle Daten mit einem als Prodrug veresterten Ciclopiroxolamin-Derivat, bei dem eine antitumoröse Wirkung nachgewiesen wurde [ 51 , 52 ]. Auch im Bereich der Brusthaut wurde an Ex-vivo-Humanhaut in flächiger Anwendung durch Microneedling und den Einsatz von Mikroemulsionen versucht, Celecoxib topisch zu applizieren, um einen präventiven Effekt bei Mammakarzinomen zu erreichen [ 53 ].…”

Section: Besonderheiten Der Topischen Therapieunclassified

Therapeutische Besonderheiten bei Erkrankungen der Mamillenhaut

2022

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ZusammenfassungDie Mamillenregion ist durch besondere anatomische Verhältnisse charakterisiert und lässt sich aus dermatologischer Perspektive in Brusthaut, Haut des Brustwarzenhofes (Areola) und Haut der Brustwarze (Papilla mammae) unterteilen. Im klinischen Zusammenhang sind die Brustwarzen häufig während der Stillzeit durch mechanische Beanspruchung, Milieuänderung mit Mazeration durch den Milchfluss sowie durch mikrobielle Erreger alteriert. Zudem besteht hier die Gefahr der Entwicklung einer Mastitis puerperalis. Außerhalb der Schwangerschaft und Stillzeit finden sich gelegentlich an der Mamillenhaut Ekzemerkrankungen, häufig bei atopischer Disposition (atopisches Mamillenekzem) oder als irritatives Kontaktekzem („joggers nipple“). Seltener werden allergische Kontaktekzeme auf Konservierungsstoffe von Topika oder Metallen (Piercings) beobachtet. Auch im Rahmen einer Skabiesinfestation wird eine Beteiligung der Mamillen, insbesondere bei Frauen, regelmäßig beobachtet. Von großer klinischer Bedeutung sind seltene, präinvasive Läsionen eines Mammakarzinoms oder der Morbus Paget der Mamille vom extramammären Typ. Durch die besonderen anatomischen Gegebenheiten ist es naheliegend, dass bei der Anwendung von Topika sich auch spezifische Penetrationsbedingungen ableiten. Experimentelle Untersuchungen an Humanhaut ex vivo legen nahe, dass in Abhängigkeit von der Molmasse und der Löslichkeit des Arzneistoffs sowie des eingesetzten Vehikelsystems eine deutliche Zunahme der kutanen Bioverfügbarkeit, insbesondere an der Brustwarze selbst durch den transpapillären Diffusionsweg, auftreten kann. Dies sollte insbesondere bei der topischen Anwendung von Arzneistoffen mit bekanntem dosisabhängigem Nebenwirkungspotenzial (z. B. Glukokortikoiden) beachtet werden. Allerdings fehlt dafür bisher eine klinische Evidenz.

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Breast intraductal nanoformulations for treating ductal carcinoma in situ II: Dose de-escalation using a slow releasing/slow bioconverting prodrug strategy

Cited by 6 publications

References 62 publications

Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short‐term vs long‐term survivors of glioblastoma

Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short‐term vs long‐term survivors of glioblastoma

Intraductal administration of transferrin receptor-targeted immunotoxin clears ductal carcinoma in situ in mouse models of breast cancer—a preclinical study

Therapeutische Besonderheiten bei Erkrankungen der Mamillenhaut

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