Profiling peptides and methods for sensitivity profiling

Abstract

The present disclosure is generally directed to profiling peptides, compositions, and kits, as well as methods of use thereof. The profiling peptides comprise an Mcl-1 binding domain, and optionally a cellular uptake moiety. The methods of using such profiling peptides include predicting sensitivity of a cancer, selecting a treatment, treating a cancer, producing a sensitivity profile, and the like.

1 . A profiling peptide comprising a cellular uptake moiety and an Mcl-1 binding domain, the Mcl-1 binding domain having the sequence of SEQ ID NO: 1 with 0-8 modifications. 
     
     
         2 . The profiling peptide of  claim 1 , wherein the Mcl-1 binding domain has the sequence of SEQ ID NO: 1 with 0-6 modifications. 
     
     
         3 . (canceled) 
     
     
         4 . The profiling peptide of  claim 1 , wherein the Mcl-1 binding domain has the sequence of SEQ ID NO: 1 with 0-3 modifications. 
     
     
         5 - 9 . (canceled) 
     
     
         10 . The profiling peptide of  claim 1 , wherein each modification is independently a conservative amino acid substitution, addition, or deletion. 
     
     
         11 - 14 . (canceled) 
     
     
         15 . The profiling peptide of  claim 1 , wherein the cellular uptake moiety comprises at least five contiguous amino acids from a transduction domain of a human immunodeficiency virus (HIV) Trans-Activator of Transcription (TAT) peptide. 
     
     
         16 . The profiling peptide of  claim 1 , wherein the cellular uptake moiety has at least 90% identity with SEQ ID NO: 12. 
     
     
         17 . (canceled) 
     
     
         18 . The profiling peptide of  claim 1 , wherein the cellular uptake moiety comprises at least five contiguous amino acids from an Atennapedia plasma membrane (ANT) translocation domain; or
 wherein the cellular uptake moiety comprises 3-10 contiguous arginine residues.   
     
     
         19 - 24 . (canceled) 
     
     
         25 . The profiling peptide of  claim 1 , wherein the cellular uptake moiety is conjugated via a linker to the Mcl-1 binding domain. 
     
     
         26 - 28 . (canceled) 
     
     
         29 . The profiling peptide of  claim 1 , comprising the sequence of SEQ ID NO: 14 or SEQ ID NO: 15. 
     
     
         30 . (canceled) 
     
     
         31 . A composition comprising the profiling peptide of  claim 1  and a carrier. 
     
     
         32 - 40 . (canceled) 
     
     
         41 . A method for treating a cancer in a subject in need thereof, the method comprising administering a treatment regimen comprising a therapeutic agent to a subject having an Mcl-1 dependency percentage of at least 15%, the Mcl-1 dependency percentage having been obtained by an in vitro method comprising contacting a first portion of a plurality of cancer cells with a profiling peptide of  claim 1 . 
     
     
         42 . The method of  claim 41 , wherein the in vitro method further comprises detecting a change in mitochondrial integrity of the plurality of cancer cells. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 41 , wherein the subject has an Mcl-1 dependency percentage of at least 20%. 
     
     
         45 . The method of  claim 41 , wherein the subject has an Mcl-1 dependency percentage of at least 30%. 
     
     
         46 . The method of  claim 41 , wherein the subject has an Mcl-1 dependency percentage of at least 40%. 
     
     
         47 . The method of  claim 41 , wherein the therapeutic agent is a Cyclin-dependent kinase 9 (CDK9) inhibitor. 
     
     
         48 . The method of  claim 47 , wherein the CDK9 inhibitor is Alvocidib. 
     
     
         49 . The method of  claim 41 , further comprising administering Ara-C or Mitoxanthrone, or both. 
     
     
         50 . The method of  claim 41 , further comprising administering a Bcl-2 inhibitor. 
     
     
         51 . The method of  claim 50 , wherein the Bcl-2 inhibitor is Venetoclax. 
     
     
         52 . The method of  claim 41 , further comprising administering Ara-C or Daunorubicin, or both. 
     
     
         53 . The method  claim 41 , further comprising administering a Brd4 inhibitor or a DNA methyltransferase inhibitor, or both. 
     
     
         54 . The method of  claim 41 , wherein the in vitro method further comprises contacting at least the first portion of the plurality of cancer cells with a diterpenoid. 
     
     
         55 - 59 . (canceled) 
     
     
         60 . The method of  claim 42 , wherein the change in mitochondrial integrity is measured using a detecting agent. 
     
     
         61 - 64 . (canceled) 
     
     
         65 . The method of  claim 60 , wherein the detecting agent is a 3,3′-Dihexyloxacarbocyanine Iodide (DiOC6). 
     
     
         66 . The method of  claim 60 , wherein the detecting agent is a potentiometric dye. 
     
     
         67 . (canceled) 
     
     
         68 . The method of  claim 41 , wherein the plurality of cancer cells is from a hematologic cancer. 
     
     
         69 . The method of  claim 68 , wherein the hematologic cancer is multiple myeloma, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, chronic lymphogenous leukemia, chronic lymphocytic leukemia (CLL), mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, or non-Hodgkin's lymphoma. 
     
     
         70 . The method of  claim 69 , wherein the hematologic cancer is acute myeloid leukemia (AML). 
     
     
         71 - 121 . (canceled)