H. Lee Moffitt Cancer Center and Research Institute, Inc.

The University of Arizona

U.S. Bioscience, Inc.

Other

University of South Florida

Lixte Biotechnology, Inc.

Medimmune Oncology, Inc.

Alan F List

Sheng Wei

John S Kovach

Haitao Ji

Robert L Capizzi

David A Sallman

Mark L McLaughlin

Daniel Abate-Daga

Mark Gerard Schippits

Lubomir Sokol

Disclosed herein are small molecule pyrin-domain targeted NLRP3 inflammasome inhibitors.

Small molecule pyrin-domain targeted NLRP3 inflammasome inhibitors

Peptides useful as inflammasome inhibitors are disclosed and can comprise an H2 helix of a pyrin domain, wherein at least two non-consecutive amino acids of the H2 helix are covalently linked. Methods of treating a subject with a disease comprising administering to the subject the disclosed peptides are also disclosed. Further, disclosed herein are methods of inhibiting binding between a first polypeptide comprising a pyrin domain and a second polypeptide comprising a pyrin domain, the method comprising contacting either the first polypeptide or the second polypeptide with the disclosed peptides.

Stapled H2 pyrin peptides

Myelodysplastic syndrome (MDS) hematopoietic stem and progenitor cells (HSPC) translocate endosomal Toll-Like receptor (TLR)-9 to the plasma membrane, thereby sensitizing these clonal propagating cells to respective ligands in the microenvironment. TLR9 is the cognate receptor for RNA:DNA hybrids (R-loops) and unmethylated CpG oligonucleotides in oxidized mitochondrial DNA, the latter of which is abundant in the bone marrow microenvironment as a result of massive medullary pyroptotic cytolytic cell death. Both ligands are important danger-associated molecular patterns (DAMPs) triggering innate immune activation and chronic inflammation that contributes to MDS pathogenesis. In an effort to neutralize these DAMPs and disrupt this feed-forward inflammatory cascade, a chimeric protein was designed fusing the external epitopes of TLR9 to the Fc domain of human IgG4 to serve as a decoy receptor or ligand trap recognizing extracellular RNA:DNA hybrids (R-loops) and oxidized mitochondrial DNA.

TLR9 ligand trap

Disclosed are compositions and methods for treating disease or condition caused or exacerbated by S100A9 activity, such as myelodysplastic syndromes (MDS) using a composition comprising an effective amount of a CD33/S100A9 inhibitor.

Soluble CD33 for treating myelodysplastic syndromes (MDS)

Methods, systems, and apparatus, including computer programs encoded on a computer storage medium are provided, including a method for presenting information for treating patients. The method comprises presenting, in a user interface, a pathway for use in treating a patient with a disease and including a combination of therapeutic and diagnostic pathway elements including an integration of diagnostic, radiation, chemotherapy, surgical and other elements. The method further comprises augmenting the pathway including providing controls for accessing additional information associated with a given pathway element, augmenting pathway elements to include indicators for pricing, efficacy and/or toxicity of a treatment associated with a given treatment element, and augmenting the pathway with a connection to another pathway including providing a link to another pathway at a point in a given pathway that provides information for a related pathway. The method further comprises presenting an augmented pathway to a patient or treating physician.

Pathways for treating patients

The present disclosure relates to a method for diagnosing in a subject the progression from myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML). Also disclosed are methods of treating AML in a subject diagnosed by the disclosed methods.

PD1 and PDL-1 expression during progression from myelodysplastic syndrome to acute myelogenous leukemia

Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill cancer cells that express TLR9 on their surface. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a TLR9-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

TLR9-binding chimeric antigen receptors

Disclosed are methods for diagnosing a myelodysplastic syndrome (MDS) in a subject. In some embodiments, the method involves assaying a sample from the subject to detect inflammasome activation, wherein an increase in inflammasome activation in the sample compared to a control is an indication of MDS in the subject. The disclosed methods can further involve treating the subject for MDS if an increase in inflammasome activation is detected.

Inflammasome activation in myelodysplastic syndromes

Disclosed are compositions and methods for targeted treatment of cancers, such as TLR9-expressing cancers. In particular, molecules containing a TLR9 targeting ligand, such as a CpG oligodeoxynucleotide, that target lytic peptides to TLR9-expressing malignant cells are disclosed.

TLR9 targeted therapeutics

A method is disclosed for diagnosing multiple myeloma or myelodysplastic syndrome (MDS) in a subject and/or predicting the responsiveness of a patient with a multiple myeloma or MDS to lenalidomide treatment, erythropoietin treatment, or a combination thereof. The method involves assaying a biological sample from the subject, such as a blood, serum, or plasma sample, for s100A9 protein levels, TNF? levels, or a combination thereof wherein elevated levels of s100A9 in the biological sample and/or reduced levels of TNF? levels is an indication of MDS in the subject and/or that the patient will be responsive.

S100A9 levels for predicting lenalidomide and erythropoietin responsiveness

Disclosed are methods for treating a meylodysplastic syndrome (MDS) in a subject that involves administering to the subject a therapeutically effective amount of an inflammasome inhibitor. Also disclosed are methods for diagnosing a myelodysplastic syndrome (MDS) in a subject. In some embodiments, the method involves assaying a sample from the subject to detect inflammasome activation, wherein an increase in inflammasome activation in the sample compared to a control is an indication of MDS in the subject. In some embodiments, the method involves assaying a sample from the subject to detect s100A9 protein levels, wherein an increase in s100A9 protein levels in the sample compared to a control is an indication of MDS in the subject. The disclosed methods can further involve treating the subject for MDS if an increase in inflammasome activation and/or s100A9 levels are detected.

Disclosed are molecules for treating non-del(5q) MDS that mimic allelic deficiency in del5q MDS to sensitize the malignant clones of patient without del(5q). The disclosed molecule contains an inhibitor of Cdc25C, an inhibitor of PP2Ac&#x3b1;, or a combination thereof, and a toll like receptor-9 (TLR9) targeting ligand. The molecule can also contain lenalidomide, or an analogue or derivative thereof. Also disclosed is a composition comprising the disclosed molecule in a pharmaceutically acceptable carrier. Also disclosed is a method for treating non-del(5q) meylodysplastic syndrome (MDS) in a subject by administering to the subject a therapeutically effective amount of the disclosed pharmaceutical composition.

Targeted sensitization of non-del(5q) malignant cells

Disclosed herein is a method of using erythroid expression levels of RNF41 as a predictive biomarker for responsiveness to lenalidomide (LEN) in patients with non-del(5q) MDS.

RNF41 as a biomarker predicting response to lenalidomide in non-del(5q) MDS

Disclosed are methods for treating a meylodysplastic syndrome (MDS) in a subject that involves administering to the subject a therapeutically effective amount of a protein phosphatase 2A (PP2A) inhibitor.

Growing community of inventors

Tampa, FL, United States of America

Alan F List