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Publication Number
US-11844772-B2
Publication Date
2023-12-19
Expiration Date
Abstract
The methods include treating atypical teratoid/rhabdoid tumor by administration of HydroxyUreaMethyl Acylfulvene. Some embodiments relate to treatment of atypical teratoid/rhabdoid tumor by administration of HydroxyUreaMethyl Acylfulvene to a population or subject expressing SMARCB1.
Core Innovation
The document describes treating atypical teratoid/rhabdoid tumors (AT/RT) and related rhabdoid-feature cancers by administering HydroxyUreaMethyl Acylfulvene (LP-184) having negative chirality or negative optical activity to a subject in need thereof. The treated cancer is marked by deletions or alterations of SMARCB1.
Subject selection is grounded in SMARCB1/SWI/SNF chromatin remodeling complex deficiency or reduced, low, or absent functional activity, including SMARCB1 protein and nuclear localization status, SMARCB1 gene expression level, SMARCB1 protein expression, and SMARCB1 deletions or alterations as determined using approaches such as FISH, DNA sequencing, and immunohistochemistry. The document also describes determining LP-184 sensitivity and selecting patients using SMARCB1-based expression or transcription standards.
The document further describes optional combination with radiation therapy, including whole-organ irradiation, fractionated radiotherapy, radiosurgery, or combinations thereof. It also includes a kit concept for determining sensitivity using SMARCB1 expression or transcription standards with threshold and target screening levels, and provides preclinical evidence of LP-184 sensitivity across AT/RT cell lines and tumor regression in an NOD SCID CHLA-06 xenograft model following intravenous dosing.
Claims Coverage
The partial content identifies two independent claims. The first covers a biomarker-defined treatment method using a negative-chirality HydroxyUreaMethyl Acylfulvene for AT/RT marked by SMARCB1 deletions or alterations, and the second covers a prognostic scoring method using SMARCB1 expression together with administering the same negative-optical-activity HydroxyUreaMethyl Acylfulvene to a patient with a prior prostate cancer history.
Negative chirality HydroxyUreaMethyl Acylfulvene for SMARCB1 deletion/alteration AT/RT
Administering an effective amount of HydroxyUreaMethyl Acylfulvene having a negative chirality to treat an atypical teratoid/rhabdoid tumor, wherein the cancer is marked by deletions or alterations of SMARCB1.
SMARCB1 expression score prognosis guiding HydroxyUreaMethyl Acylfulvene treatment after prior prostate cancer treatment
Measuring expression levels of SMARCB1 in a patient sample, prognosing increased likelihood of cancer recurrence or cancer-specific death based on the test expression score exceeding a reference expression score, and administering a treatment comprising an effective amount of HydroxyUreaMethyl Acylfulvene having a negative optical activity for the atypical teratoid/rhabdoid tumor in a patient previously treated for prostate cancer.
Across the independent claims, coverage centers on AT/RT treatment using HydroxyUreaMethyl Acylfulvene with negative chirality or negative optical activity, with patient selection and/or prognosis based on SMARCB1 expression status, SMARCB1 deletions or alterations, and SMARCB1-based expression scoring relative to a reference population.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating atypical teratoid/rhabdoid tumors (AT/RT) and related rhabdoid-feature cancers by administering negative-chirality HydroxyUreaMethyl Acylfulvene (LP-184).
Selecting patients for LP-184 treatment based on SMARCB1/SWI/SNF complex deficiency or reduced, low, or absent functional activity, including SMARCB1 gene or protein expression status and SMARCB1 alterations or deletions.
Determining LP-184 sensitivity using a kit that uses SMARCB1 expression or transcription standards with threshold and target screening levels.
Providing a prognostic approach using SMARCB1 expression scoring to predict increased likelihood of cancer recurrence or cancer-specific death and to guide administration of negative-optical-activity HydroxyUreaMethyl Acylfulvene.
Combining HydroxyUreaMethyl Acylfulvene treatment with radiation therapy modalities such as whole-organ irradiation, fractionated radiotherapy, radiosurgery, or combinations thereof.
Preclinical evaluation of LP-184 sensitivity across AT/RT cell lines and tumor regression in an NOD SCID CHLA-06 xenograft model following intravenous dosing.
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