S100a1 protein-derived peptide for use in treating cancer or in treating or preventing antineoplastic agent-mediated cytotoxicity, cancer therapy-related cardiac dysfunction or cancer therapy related heart failure

Abstract

The present invention pertains to a peptide of the S100A1 protein for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF), as well as nucleic acids encoding said peptide, vectors comprising said nucleic acid, host cells comprising the vector or nucleic acid and expressing it, and to respective pharmaceutical compositions.

Description

[0001] Most, Patrick et al.

[0002] 1275-2 PCT

[0003] S100A1 PROTEIN-DERIVED PEPTIDE FOR USE IN TREATING CANCER OR IN TREATING OR PREVENTING ANTINEOPLASTIC AGENT-MEDIATED CYTOTOXICITY, CANCER THERAPY-RELATED CARDIAC DYSFUNCTION OR CANCER THERAPY RELATED HEART FAILURE

[0004] The present invention relates to a peptide derived from S100A1 protein and nucleic acids encoding the same for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF), as well as to vectors comprising said nucleic acid and to respective pharmaceutical compositions.

[0005] BACKGROUND OF THE INVENTION

[0006] Antineoplastic therapies, with their cytotoxic mechanisms of action, lead to frequent undesirable damage of e.g. the heart muscle, which, as a terminally differentiated tissue, has no substantial regeneration potential (Linders et al., NPJ Aging 2024; 10( 1):9; Lyon et al., Eur Heart J 2022; 43(41):4229-4361). As an example, the chemotherapeutic agent doxorubicin from the anthracycline class of drugs, which is clinically used against solid tumors, leads to the development of so-called cancer therapy-related cardiac dysfunction (CTRCD) in up to 9% of treated patients (Linders et al., 2024 and Lyon et al., 2022). Dexrazoxane hydrochloride (also referred to as Zinecard or Cardioxane) is an EDTA derivative and FDA and EMA approved cytoprotective agent that mitigates the risk of doxorubicine-mediated cytotoxicity. It is, however, suspected to favor the development of secondary malignancies.

[0007] The S100A1 protein is a homodimer and a member of the EF-hand calcium (Ca2+) sensor protein superfamily, which comprises at least 20 paralogs (Ritterhoff and Most, Gene Ther. 2012; 19:613-621). S100A1 is expressed in a tissue- and cell-specific manner with highest abundance in cardiac and skeletal muscle, where it resides at the sarcoplasmic reticulum (SR), the sarcomere and within the mitochondria of myocytes (Most et al. Am J Physiol Regul Integr Comp Physiol. 2007; 293:R568-577). In vitro and in vivo genetic gain- and loss-of function studies have shown that S100A1 plays a decisive role as a molecular enhancer of heart and skeletal muscle contractile performance (Kraus et al. J Mol Cell Cardiol. 2009; 47:445-455). This is due in part to the ability of S100A1 to bind to and regulate the activity of a number of key molecular effectors including the SR Ca2+ATPase (SERCA2a), the ryanodine receptor (RyR) 1 and 2, mitochondrial ATP synthase (Fl-ATPase) and titin, all of which govern cardiac and skeletal muscle Ca2+cycling, energy supply and mechanical properties (Ritterhoff et al., 2012; Most et al., 2007; Kraus et al., 2009).

[0008] Dowarha et al. (PLoS ONE 2020; 15(6): e0234152) synthesized a 17-residue peptide derived from the S100A1 protein and attached it to the cell-penetrating HIV-TAT peptide. This construct was shown to inhibit cell proliferation and to increase the protein levels of p53 and its downstream p21 in MCF-7 cells.

[0009] US 9,428,564 and US 9,453,053 describe a S100A1 derived peptide for treating or preventing myopathies.

[0010] There remains a need for further therapeutic agents that can be used in the treatment of cancer. There remains a further need for agents that treat or prevent damage to the heart during anti -cancer therapy.

[0011] SUMMARY OF THE INVENTION

[0012] According to a first aspect, the present invention provides a peptide comprising or consisting of:

[0013] (i) the amino acid sequence YVVLVAALTVACNNFFWENS (SEQ ID NO: 1),

[0014] (ii) a fragment of the amino acid sequence according to SEQ ID NO: 1, wherein between 1 and 9 amino acids are deleted at the N-terminus of SEQ ID NO: 1, or

[0015] (iii) a variant of (i) or (ii) having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or fragment thereof, for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

[0016] According to one embodiment, the peptide for use further comprises one or more elements independently selected from the group consisting of a hydrophilic domain, an epitope-tag and a targeting domain.

[0017] According to a preferred embodiment, the peptide does not comprise a membrane penetration enhancing domain.

[0018] According to a further embodiment, the peptide consists of between 11 and 40 amino acids.

[0019] According to a further preferred embodiment, the peptide does not comprise any amino acid sequence of the human S100A protein N- and / or C-terminally of the amino acid sequence according to SEQ ID NO: 1.

[0020] In a second aspect, the present invention provides a nucleic acid encoding the peptide of the invention for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or CTRCD or CTRHF.

[0021] According to a further aspect, the present invention provides an expression vector comprising the nucleic acid of the invention for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or CTRCD or heart failure, specifically CTRHF.

[0022] According to a preferred embodiment, the nucleic acid or set of nucleic acids is operably linked to a control sequence. According to a further aspect, the present invention provides a recombinant host cell or culture of recombinant host cells comprising the nucleic acid of the invention or the expression vector of the invention for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or CTRCD or CTRHF.

[0023] According to a further aspect, the present invention provides a pharmaceutical composition comprising the peptide of the invention, the nucleic acid of the invention, the expression vector of the invention, or the host cell or culture of host cells of the invention, and a pharmaceutically acceptable excipient for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or CTRCD or CTRHF.

[0024] According to a further aspect, the present invention provides the nucleic acid of the invention, the expression vector of the invention, the host cell or culture of host cells of the invention, or the pharmaceutical composition of the invention, wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, (osteo)sarcoma, lymphoma, leukemia, myeloma, thyroid cancer, gastric cancer, colon cancer, and pancreas cancer.

[0025] According to an embodiment, the antineoplastic agent-mediated cytotoxicity is anthracycline-mediated cytotoxicity.

[0026] According to a further embodiment, the anthracycline-mediated cytotoxicity is doxorubicin-mediated cytotoxicity.

[0027] According to a preferred embodiment, the peptide, the nucleic acid or set of nucleic acids, the expression vector, the host cell or culture of host cells, or the pharmaceutical composition is administered prior to or during an antineoplastic treatment.

[0028] According to a further aspect, the present invention provides a pharmaceutical composition comprising a combination of the peptide of the present invention and at least one antineoplastic agent. According to a preferred embodiment, the pharmaceutical composition is for use in treating cancer. According to a further preferred embodiment, the antineoplastic agent is selected from doxorubicin and / or sunitinib.

[0029] According to a further aspect, the present invention provides a method of treating cancer in a subject in need thereof, wherein the method comprises the step of administering to the subject a therapeutically efficient amount of the peptide of the invention.

[0030] According to a further aspect, the present invention provides a method of treating or preventing antineoplastic agent-mediated cytotoxicity against cardiomyocytes or CTRCD or CTRHF in a subject in need thereof, the method comprising administering to the subject a therapeutically efficient amount of the peptide of the invention.

[0031] According to a preferred embodiment, the patient has received or is receiving therapy with an antineoplastic agent, preferably an anthracycline, more preferably doxorubicin.

[0032] Other features and advantages of the present invention will be apparent from the following detailed description and the claims. LIST OF FIGURES

[0033] Fig. 1 : Protective effect of SlOOAlct against doxorubicin- and sunitinib-mediated toxicity on cardiomyocytes. Fig. 1 shows that SlOOAlct peptide (10 pM) mitigates the toxic effect of (A) doxorubicin (100 nM) and (B) sunitinib (1,000 nM) on cardiomyocytes 24 hours after cell seeding. n=9 independent cell isolations and measurements. ****P=0.001 and 0 *P=0.03. Vehicle is non- cytotoxic solvent for SlOOAlct peptide (10 pM). Data are presented as mean plus / minus SEM n- fold change from control (untreated vehicle).

[0034] Fig. 2 : Selective oncolytic effect of SlOOAlct peptide on human cancer cells with equivalent potency to chemotherapeutic agents. A) Oncolytic effect on Hela and MCF7 cells. B) Reduction in the number of Hela and MCF7 cells. C) comparison of SlOOAlct (1,000 nM) with doxorubicin (Doxo) (100 nM) and sunitinib (1,000 nM) on Hela cells. D) and E) show no effect of SlOOAlct on normal non-malignant cells such as Cosl and MEF). n=10 independent measurements each. *P=0.05 SlOOAlct vs. control (vehicle). **P=0.03 SlOOAlct vs. control (vehicle). Data are presented as mean plus / minus SEM.

[0035] Fig. 3: Synergistic oncolytic activity of SlOOAlct with doxorubicin and sunitinib on cancer cells. A) Oncolytic effect of SlOOAlct (IpM) in combination with 10 nM doxorubicin on cancer cells B) Oncolytic effect of SlOOAlct (IpM) in combination with 100 nM sunitinib on cancer cells. n=4 independent measurements each. **P<0.03 SlOOAlct vs. control (vehicle). ****p<0.01 SlOOAlct vs. control (vehicle). Data are presented as mean plus / minus SEM.

[0036] Fig. 4: Toxilight Cytotoxicity BioAssay determining adenylate kinase (AK) content as degree for cell death caused by doxorubicin- and sunitinib-mediated cytotoxicity in cultured nonrefractory cardiomyocytes (NRCM). n = 18 (vehicle, SlOOAlct), 9 (doxorubicin, sunitinib). **P<0.03; ***P<0.01. Vehicle is the solvent for the SlOOAlct peptide.

[0037] Fig. 5: Results of fluorescence-coupled SlOOAlct peptide and TAT-peptide uptake in rat cardiomyocytes (Fig. 5A) and in MCF7 tumor cells (Fig. 5B). Doses in nM. Cells were incubated with FITC peptide, excess peptide was removed by washing three times, cells were lysed, and fluorescence intensity was measured.

[0038] SEQUENCES

[0039] SEP ID NO: 1 (SlOOAlct)

[0040] YVVLVAALTVACNNFFWENS

[0041] SEP ID NO: 2

[0042] APWHLSSQYSRT

[0043] SEP ID NO: 3

[0044] KKKKKKP SEO ID NO: 4

[0045] KKKKKKPGGYVVLVAALTVACNNFFWENS

[0046] SEP ID NO: 5 (human S100A1)

[0047] MGSELETAMETLINVFHAHSGKEGDKYKLSKKELKELLQTELSGFLDAQKDVDAVDKVM KELDENGDGEVDFQEYVVLVAALTVACNNFFWENS

[0048] SEQ ID NO: 6 (nucleic acid sequence encoding SlOOAlct):

[0049] TATGTGGTGCTTGTGGCTGCTCTCACAGTGGCCTGTAACAATTTCTTCTGGGAGAACAG TTGA

[0050] SEQ ID NO: 7

[0051] DKDD

[0052] SEQ ID NO: 8

[0053] DKDDPPYVVLVAALTVACNNFFWENS

[0054] DETAILED DESCRIPTION

[0055] Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0056] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Some of the documents cited herein are characterized as being “incorporated by reference”. In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence.

[0057] In the following, the elements of the present invention will be described. These elements are listed with specific embodiments; however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0058] To practice the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA techniques are employed which are explained in the literature in the field (cf., e.g., Molecular Cloning: A Laboratory Manual, 2ndEdition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989). In the following, the elements of the present invention will be described. These elements are listed with specific embodiments; however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The various described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0059] DEFINITIONS

[0060] Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", H.G.W. Leuenberger, B. Nagel, and H. Kolbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).

[0061] To practice the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, cell biology, and recombinant DNA techniques are employed which are explained in the literature in the field (cf., e.g., Molecular Cloning: A Laboratory Manual, 2ndEdition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989). Furthermore, conventional methods of clinical cardiology are employed which are also explained in the literature in the field (cf., e.g., Practical Methods in Cardiovascular Research, S. Dhein et al. eds., Springer Verlag Berlin Heidelberg, 2005).

[0062] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents, unless the content clearly dictates otherwise.

[0063] As used herein, the term “and / or” means that it refers to either one or both or all of the options cited in the context of this term. For example, when referring to “treating and / or preventing”, the term is to be interpreted to mean: 1) treating, 2) preventing, and 3) treating and preventing the indicated condition. In the context of the different aspects of present invention, the term “peptide” refers to a short polymer of amino acids linked by peptide bonds. It has the same chemical (peptide) bonds as a protein but is shorter in length. In the context of the present invention, the peptide preferably has a length of between 11 and 40 amino acids.

[0064] In the context of the different aspects of present invention, the term "protein" refers to a molecule comprising multiple amino acid residues and / or one or more polypeptides that resume a secondary and tertiary structure and additionally refers to a protein that is made up of several polypeptides, i.e. several subunits, forming quaternary structures. The protein has sometimes nonpeptide groups attached, which can be called prosthetic groups or cofactors.

[0065] The terms “polynucleotide” and “nucleic acid” are used synonymously and are understood as single or double-stranded oligo- or polymers of deoxyribonucleotide or ribonucleotide bases or both. The depiction of a single strand of a nucleic acid also defines (at least partially) the sequence of the complementary strand. The nucleic acid may be single or double stranded, or it may contain portions of both double and single stranded sequences. In the context of the different aspects of present invention, the term nucleic acid comprises cDNA, genomic DNA, recombinant DNA, cRNA and mRNA. A nucleic acid may consist of an entire gene, or a portion thereof, the nucleic acid may also be a microRNA (miRNA) or small interfering RNA (siRNA). The term “oligonucleotide” when used in the context of one of the different aspects of present invention, refers to a nucleic acid of up to about 50 nucleotides, e.g. 2 to about 50 nucleotides in length. “Nucleic acid” molecules are understood as a polymeric or oligomeric macromolecule made from nucleotide monomers. Nucleotide monomers are composed of a nucleobase, a five-carbon sugar (such as but not limited to ribose or 2'-deoxyribose), and one to three phosphate groups. Typically, a polynucleotide is formed through phosphodiester bonds between the individual nucleotide monomers. In the context of the present invention, nucleic acid molecules include but are not limited to ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and mixtures thereof such as e.g. RNA-DNA hybrids. The nucleic acid may be obtained by biological, biochemical or chemical synthesis methods or any of the methods known in the art. The nucleic acids, can e.g. be synthesized chemically, e.g. in accordance with the phosphotriester method (see, for example, Uhlmann, E. & Peyman, A. (1990) Chemical Reviews, 90, 543-584). "Aptamers" are nucleic acids which bind with high affinity to a polypeptide. Aptamers can be isolated by selection methods from a large pool of different single-stranded RNA molecules (see e.g. Jayasena Clin. Chem. 1999, 45, 1628-50; Klug and Famulok M. Mol. Biol. Rep. 1994; 20, 97-107; US 5,582,981). Aptamers can also be synthesized and selected in their mirror-image form, for example as the L-ribonucleotide (Nolte et al. Nat. Biotechnol. 1996; 14, 1116-9; Klussmann et al. Nat. Biotechnol. 1996; 14, 1112- 5). Forms which have been isolated in this way enjoy the advantage that they are not degraded by naturally occurring ribonucleases and, therefore, possess greater stability. Nucleic acids may be degraded by endonucleases or exonucleases, in particular by DNases and RNases which can be found in the cell. It is, therefore, advantageous to modify the nucleic acids in order to stabilize them against degradation, thereby ensuring that a high concentration of the nucleic acid is maintained in the cell over a long period of time (Beigelman et al. Nucleic Acids Res. 1995; 23:3989-94). Typically, such stabilization can be obtained by introducing one or more intemucleotide phosphorus groups or by introducing one or more non-phosphorus intemucleotides. Suitable modified intemucleotides are compiled in Uhlmann and Peyman 1990, supra (see also Beigelman et al. Nucleic Acids Res. 1995; 23:3989-94). Modified intemucleotide phosphate radicals and / or non-phosphoms bridges in a nucleic acid which can be employed in one of the uses according to the invention contain, for example, methyl phosphonate, phosphorothioate, phosphoramidate, phosphorodithioate and / or phosphate esters, whereas non-phosphoms intemucleotide analogues contain, for example, siloxane bridges, carbonate bridges, carboxymethyl esters, acetamidate bridges and / or thioether bridges. It is also the intention that this modification should improve the durability of a pharmaceutical composition which can be employed in one of the uses according to the invention.

[0066] As used herein, the term “vector” refers to a protein or a polynucleotide or a mixture thereof which is capable of being introduced or of introducing the proteins and / or nucleic acid comprised therein into a cell. In the context of the present invention, it is preferred that the genes of interest encoded by the introduced polynucleotide are expressed within the cell upon introduction of the vector or vectors. Examples of suitable vectors include but are not limited to plasmids, cosmids, phages, vimses or artificial chromosomes.

[0067] As used herein, the term "variant" is to be understood as a polynucleotide or peptide which differs in comparison to the polynucleotide or peptide from which it is derived by one or more changes in its length or sequence. The peptide or polynucleotide from which a peptide or nucleic acid variant is derived is also known as the parent peptide or polynucleotide. The term “variant” comprises “fragments” or “derivatives” of the parent molecule. Typically, “fragments” are smaller in length or size than the parent molecule, whilst “derivatives” exhibit one or more differences in their sequence in comparison to the parent molecule.

[0068] Also encompassed are modified molecules such as but not limited to post-translationally modified peptides (e.g., glycosylated, biotinylated, phosphorylated, ubiquitinated, palmitoylated, or proteolytically cleaved proteins) and modified nucleic acids such as methylated DNA. Also, mixtures of different molecules such as but not limited to RNA-DNA hybrids. Typically, a variant is constructed artificially, preferably by gene-technological means whilst the parent polypeptide or polynucleotide is a wild-type protein or polynucleotide. However, also naturally occurring variants are to be understood to be encompassed by the term "variant" as used herein. Further, the variants usable in the present invention may also be derived from homologs, orthologs, or paralogs of the parent molecule or from artificially constructed variant, provided that the variant exhibits at least one biological activity of the parent molecule, e.g., is functionally active.

[0069] As used herein, the term peptide “variant” is to be understood as a peptide which differs in comparison to the peptide from which it is derived by one or more changes in the amino acid sequence. The peptide from which a peptide variant is derived is also known as the parent peptide. Typically, a variant is constructed artificially, preferably by gene-technological means. The variants usable in accordance with the present invention may also be derived from homologs, orthologs, or paralogs of the parent peptide or from artificially constructed variants, provided that the variant exhibits at least one biological activity of the parent peptide. The changes in the amino acid sequence may be amino acid exchanges, insertions, deletions, N-terminal truncations, or C- terminal truncations, or any combination of these changes, which may occur at one or several sites. The amino acid exchanges may be conservative and / or non-conservative.

[0070] Semi-conservative and especially conservative amino acid substitutions, wherein an amino acid is substituted with a chemically related amino acid are preferred. Typical substitutions are among the aliphatic amino acids, among the amino acids having aliphatic hydroxyl side chain, among the amino acids having acidic residues, among the amide derivatives, among the amino acids with basic residues, or the amino acids having aromatic residues. Typical semi-conservative and conservative substitutions are:

[0071] Amino acid Conservative substitution Semi-conservative substitution

[0072] A G; S; T N; V; C

[0073] C A; V; L M; I; F; G

[0074] D E; N; Q A; S; T; K; R; H

[0075] E D; Q; N A; S; T; K; R; H

[0076] F W; Y; L; M; H I; V; A

[0077] G A S; N; T; D; E; N; Q

[0078] H Y; F; K; R L; M; A

[0079] I V; L; M; A F; Y; W; G

[0080] K R; H D; E; N; Q; S; T; A

[0081] L M; I; V; A F; Y; W; H; C

[0082] M L; I; V; A F; Y; W; C;

[0083] Q N D; E; A; S; T; L; M; K; R

[0084] R K; H N; Q; S; T; D; E; A

[0085] S A; T; G; N D; E; R; K

[0086] T A; S; G; N; V D; E; R; K; I

[0087] V A; L; I M; T; C; N w F; Y; H L; M; I; V; C

[0088] Y F; W; H L; M; I; V; C Changing from A, F, H, I, L, M, P, V, W or Y to C is semi-conservative if the new cysteine remains as a free thiol. Furthermore, the skilled person will appreciate that glycines at sterically demanding positions should not be substituted and that P should not be introduced into parts of the protein which have an alpha-helical or a beta-sheet structure.

[0089] Alternatively or additionally, a “variant” as used herein, can be characterized by a certain degree of sequence identity to the parent peptide or parent polynucleotide from which it is derived. More precisely, a protein variant in the context of the present invention exhibits at least 90% sequence identity to its parent peptide. A polynucleotide variant in the context of the present invention exhibits at least 80% sequence identity to SEQ ID NO: 6. According to a preferred embodiment, the parent polypeptide comprises or consists of SEQ ID NO: 1.

[0090] Variants may additionally or alternatively comprise deletions of amino acids, which may be N-terminal truncations, C-terminal truncations or internal deletions or any combination of these. Such variants comprising N-terminal truncations, C-terminal truncations and / or internal deletions are referred to as “deletion variants” in the context of the present application.

[0091] Fragments may be naturally occurring (e.g. splice variants) or it may be constructed artificially, preferably by gene-technological means. According to the present invention, a fragment comprises at least 11 amino acids of SEQ ID NO: 1. Preferably, a fragment or deletion variant has a deletion of up to 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids compared to SEQ ID NO: 1, preferably at the N-terminus and / or internally as compared to the parent peptide of SEQ ID NO: 1, more preferably at its N-terminus. In cases where a fragment sequence is compared with SEQ ID NO: 1, the sequence identity percentage is to be calculated with reference to the fragment, i.e. the shorter of the two sequences to be compared. The sequence identity is then determined on the basis of the overlap between the fragment and SEQ ID NO: 1. The percentage of sequence identity is preferably determined via sequence alignments. Such alignments can be carried out with several art-known algorithms. For example, the grade of sequence identity (sequence matching) may be calculated using e.g. BLAST (blastp) or EMBOSS Needle (EMBL-European Bioinfomratics Institute). A respective algorithm is incorporated into the BLASTN and BLASTP programs of Altschul et al. J. Mol. Biol. 1990; 215: 403-410, and in Altschul et al. Nucleic Acids Res. 1997; 25: 3389-3402.

[0092] Fragments of SEQ ID NO: 1 that additionally comprise one or more amino acid substitutions within their amino acid sequence compared to SEQ ID NO: 1 are also referred to as “deletion variants”.

[0093] Additionally or alternatively, a deletion variant may occur not due to structural deletions of the respective amino acids as described above, but due to these amino acids being inhibited or otherwise not able to fulfill their biological function. Typically, such functional deletion occurs due to the insertions to or exchanges in the amino acid sequence that changes the functional properties of the resultant protein, such as but not limited to alterations in the chemical properties of the resultant peptide (i.e. exchange of hydrophobic amino acids to hydrophilic amino acids), alterations in the post-translational modifications of the resultant protein (e.g. post-translational cleavage or glycosylation pattern), or alterations in the secondary or tertiary protein structure. Additionally or alternatively, a functional deletion may also occur due to transcriptional or post-transcriptional gene silencing (e.g. via siRNA) or the presence or absence of inhibitory molecules such as but not limited to protein inhibitors or inhibitory antibodies.

[0094] As used herein, an “individual”, “patient” or “subject” means any mammal, reptile or bird that may benefit from the present invention. Preferably, an “individual”, “patient” or “subject” is selected from the group consisting of animals such as e.g. mouse, rat or rabbit) domestic animals (including e.g. guinea pig, rabbit, horse, donkey, cow, sheep, goat, pig, chicken, duck, camel, cat, dog, turtle, tortoise, snake, or lizard), or primates including chimpanzees, bonobos, gorillas and human beings. It is particularly preferred that an “individual”, “patient” or “subject” is a human being.

[0095] The term “patient” as used herein further refers to any mammal, reptile or bird that may benefit from a prognosis, diagnosis, identification or treatment of a disease or disorder. Preferably, a “patient” is selected from the group consisting of laboratory animals (e.g. mouse or rat), domestic animals (including e.g. guinea pig, rabbit, horse, donkey, cow, sheep, goat, pig, chicken, camel, cat, dog, turtle, tortoise, snake, or lizard), or primates including chimpanzees, bonobos, gorillas and human beings. It is particularly preferred that the “patient” is a human being.

[0096] The terms “disease” and “disorder” are used interchangeably herein, referring to an abnormal condition, especially an abnormal medical condition such as an illness or injury, wherein a tissue, an organ or an individual is not able to efficiently fulfil its function anymore. Typically, but not necessarily, a disease is associated with specific symptoms or signs indicating the presence of such disease. The presence of such symptoms or signs may thus, be indicative for a tissue, an organ or an individual suffering from a disease. An alteration of these symptoms or signs may be indicative for the progression of such a disease. A progression of a disease is typically characterised by an increase or decrease of such symptoms or signs which may indicate a “worsening” or “bettering” of the disease. The “worsening” of a disease is characterised by a decreasing ability of a tissue, organ or organism to fulfil its function efficiently, whereas the “bettering” of a disease is typically characterised by an increase in the ability of a tissue, an organ or an individual to fulfil its function efficiently. A tissue, an organ or an individual being at “risk of developing” a disease is in a healthy state but shows potential of a disease emerging. Typically, the risk of developing a disease is associated with early or weak signs or symptoms of such disease. In such case, the onset of the disease may still be prevented by treatment.

[0097] “Symptoms” of a disease are implications of the disease noticeable by the tissue, organ or organism having such disease and include but are not limited to pain, weakness, tenderness, strain, stiffness, and spasm of the tissue, an organ or an individual. “Signs” or “signals” of a disease include but are not limited to the change or alteration such as the presence, absence, increase or elevation, decrease or decline, of specific indicators such as biomarkers or molecular markers, or the development, presence, or worsening of symptoms.

[0098] A disorder may be acquired or congenital. In this context, the term “acquired” means that the medical condition, i.e., the disorder, developed post-fetally.

[0099] As used herein, “treat”, “treating” or “treatment” of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in an individual that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in individuals that were previously symptomatic for the disorder(s).

[0100] As used herein, “prevent”, “preventing”, “prevention”, “prophylaxis” of a disease or disorder means preventing that such disease or disorder occurs in the patient.

[0101] As used herein, “administering” includes in vivo administration, as well as administration directly to tissue ex vivo, such as vein grafts.

[0102] An “effective amount” or a “therapeutically effective amount” is an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration. The effective amount in each individual case may be determined empirically by a skilled artisan according to established methods in the art.

[0103] The terms “pharmaceutical” e.g. in the context of a pharmaceutical composition, “medicament” and “drug” are used interchangeably herein referring to a substance and / or a combination of substances being used for the identification, prevention or treatment of a tissue status or disease.

[0104] “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "pharmaceutically acceptable salt" refers to a salt of the protein or peptide of the present invention. Suitable pharmaceutically acceptable salts include acid addition salts which may, for example, be formed by mixing a solution of the peptide of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the peptide carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- ethane sulfonate, hydroxynaphthoate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3 -phenylpropionate, phosphate / diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, S. M. Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci., 66, pp. 1-19 (1977)).

[0105] The term “active ingredient” refers to the substance in a pharmaceutic formulation that is biologically active, i.e. that provides pharmaceutical value. A pharmaceutical composition may comprise one or more active ingredients which may act in conjunction with or independently of each other. The active ingredient can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as but not limited to those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

[0106] Whether or not a fragment or variant of the peptide in accordance with the present invention is biologically active can, for example, be determined by any one of the tests described in the examples below. According to a preferred embodiment, a fragment or variant of the peptide in accordance with the invention is biologically active if the results obtained with such fragment or variant compared to the results obtained with the peptide of the present invention shown in at least one of the examples presented herein below achieve at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or 100% of the effect reported for the peptide over the indicated controls.

[0107] The terms “preparation” and “composition” are intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

[0108] The term “carrier”, as used herein, refers to a pharmacologically inactive substance such as but not limited to a diluent, excipient, or vehicle with which the therapeutically active ingredient is administered. Such pharmaceutical carriers can be liquid or solid. Liquid carriers include but are not limited to sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. A saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

[0109] Suitable pharmaceutical "excipients" include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0110] The term “adjuvant” refers to agents that augment, stimulate, activate, potentiate, or modulate the immune response to the active ingredient of the composition at either the cellular or humoral level, e.g. immunologic adjuvants stimulate the response of the immune system to the actual antigen, but have no immunological effect themselves. Examples of such adjuvants include but are not limited to inorganic adjuvants (e.g. inorganic metal salts such as aluminium phosphate or aluminium hydroxide), organic adjuvants (e.g. saponins or squalene), oil-based adjuvants (e.g. Freund’s complete adjuvant and Freund’s incomplete adjuvant), cytokines (e.g. IL-ip, IL-2, IL-7, IL-12, IL-18, GM-CFS, and INF-y) particulate adjuvants (e.g. immuno-stimulatory complexes (ISCOMS), liposomes, or biodegradable microspheres), virosomes, bacterial adjuvants (e.g. monophosphoryl lipid A, or muramyl peptides), synthetic adjuvants (e.g. non-ionic block copolymers, muramyl peptide analogues, or synthetic lipid A), or synthetic polynucleotides adjuvants (e.g. polyarginine or poly lysine).

[0111] The term “cytostatic drug” (also referred to as cytotoxic agent) as used herein is well known to the skilled person, and generally refers to agents of compounds that are known to be of use in chemotherapy for treating cancer. Representative cytostatic drugs include but are not limited to anthracyclines and kinase inhibitors such as tyrosine kinase inhibitors. Non-limiting examples of anthracyclines include doxorubicin, daunorubicin, idarubicin, and pirarubicin. A non-limiting example of a tyrosine kinase inhibitor is sunitinib. The term “antineoplastic agent” as used herein falls under the definition of a cytostatic drug.

[0112] EMBODIMENTS

[0113] The peptide for use of the present invention is referred to herein as SlOOAlct. It is a short peptide comprising the C-terminal helix (amino acids 75-94) of the native human S100A1 protein. A schematic drawing of the peptide comprising additionally a tag for aiding in chemical synthesis and solubility is shown in Figure 1A. It was surprisingly found that the peptide in accordance with the present invention exhibits a direct protective effect against antineoplastic agent-mediated damage to cardiomyocytes. It was further surprisingly found that the peptide in accordance with the present invention shows direct oncolytic activity on cancer cells. This allows for example reducing the use of cytostatic drugs during cancer treatment. Reducing the use can mean reducing the amount and / or dose of one or more cytostatic drugs that are used or to be used in the treatment. It was further surprisingly found that the peptide in accordance with the invention is in itself cell- permeable and does not require any further modifications or additions to permeate through cellmembranes in vitro or in vivo.

[0114] According to one aspect, the present invention provides a peptide comprising or consisting of:

[0115] (i) the amino acid sequence YVVLVAALTVACNNFFWENS (SEQ ID NO: 1),

[0116] (ii) a fragment of the amino acid sequence according to SEQ ID NO: 1, wherein between 1 and 9 amino acids are deleted at the N-terminus of SEQ ID NO: 1, or

[0117] (iii) a variant of (i) or (ii) having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or fragment thereof, for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF). Thus, the peptide of the invention can be used for treating cancer. The peptide of the invention can also be used in the treatment or prevention of antineoplastic agent- mediated cytotoxicity against cardiomyocytes. The peptide of the invention can also be used in the treatment or prevention of cancer therapy-related cardiac dysfunction (CTRCD). The peptide of the invention can also be used in the treatment or prevention of cancer therapy-related heart failure (CTRHF). According to a further preferred embodiment, the cancer therapy-related heart failure is heart failure is heart failure with reduced ejection fraction (HFrEF).

[0118] The fragment or variant of the peptide has at least 90%, at least 90.5%, at least 91%, at least 91.5%, at least 92%, at least 92.5%, at least 93%, at least 93.5%, at least 94%, at least 94.5%, at least 95%, at least 95.5%, at least 96%, at least 96.5%, at least 97%, at least 97.5%, at least 98%, at least 98.5%, or at least 99%, at least 99.5% identity to SEQ ID NO: 1. Fragments or deletion variants of SEQ ID NO: 1 have a length of between 11 and 19 amino acids of SEQ ID NO: 1.

[0119] Variants of SEQ ID NO: 1 comprise one or more amino acid substitutions in the sequence of SEQ ID NO: 1. These variants may further be truncated in that they may also comprise deletions if compared to SEQ ID NO: 1. In such a case, they are also referred to as deletion variants of SEQ ID NO: 1.

[0120] Fragments of SEQ ID NO: 1 according to the present invention differ from SEQ ID NO: 1 preferably at the N-terminus or internally and comprise one or more amino acid deletions. Fragments may additionally comprise one or more substitutions in their amino acid sequence compared to SEQ ID NO: 1. In such cases, the fragments are also referred to as deletion variants.

[0121] Preferably, the fragment or variant of SEQ ID NO: 1 maintains or exerts essentially the same biological function as the parent peptide according to SEQ ID NO: 1. Maintaining or exerting essentially the same biological function as the parent peptide according to SEQ ID NO: 1 means, in accordance with the present invention, one or more of protective activity against doxorubicin- mediated cytotoxicity as measure in Example 1 below and oncolytic activity on cancer cells as measured in accordance with Example 2 below. Maintaining or exerting essentially the same biological function as the parent peptide according to SEQ ID NO: 1 means maintaining or exhibiting the activity of the parent peptide to at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80&, at least 90%, at least 95% or at least 98%.

[0122] According to a preferred embodiment, however, the peptide in accordance with the present invention comprises or consists of the amino acid sequence of SEQ ID NO: 1. More preferably, the peptide in accordance with the present invention consists of the amino acid sequence of SEQ ID NO: 1.

[0123] According to one embodiment of the present invention, the peptide for use may additionally comprise one or more elements independently selected from the group consisting of a hydrophilic domain, an epitope-tag and a targeting domain. One or more preferably means one, two, three, or four of the elements, be it the same or different elements. Thus, in accordance with a preferred embodiment, the peptide in accordance with the present invention comprises or consists of the amino acid sequence of SEQ ID NO: 1 and one or more elements independently selected from the group consisting of a hydrophilic domain, an epitope-tag and a targeting domain. More preferably, the peptide in accordance with the present invention consists of the amino acid sequence of SEQ ID NO: 1 and one or more elements independently selected from the group consisting of a hydrophilic domain, an epitope-tag and a targeting domain.

[0124] These elements may be linked directly or indirectly to the N- or C-terminus of the peptide. Preferably, the element is linked to the peptide’s N-terminus.

[0125] An epitope is a portion of a molecule to which an antibody binds. In the context of the present invention, an epitope-tag is preferably a peptide-tag, for example, hemagglutinin-(HA-), FLAG-, myc-, or a poly-His-tag. Such an epitope-tag may be used to locate the peptide of the present invention within a cell, for example, for determining whether the peptide penetrates, z.e., traverses, cell membranes and can be found inside an intact cell incubated with said peptide.

[0126] A peptide targeting domain in the context of the present invention may be any moiety that is suitable for targeting a peptide in vivo to a specific organ or specific cells. For example, a peptide targeting domain may be a peptide that specifically binds to a particular receptor which is specific for certain cells or a certain organ. Preferably, the presence of a peptide targeting domain within the peptide according to the present invention allows for specific targeting of cells or organs in a patient to which the peptide was administered systemically. A particularly preferred tag is a cardiomyocyte-targeting peptide tag such as a tag having the sequence of APWHLSSQYSRT (SEQ ID NO: 2).

[0127] Further preferred additions include peptide tags that aid in synthesis and / or purification of the peptide of the invention. A particularly preferred tag that aids in chemical synthesis of the peptide of the invention has the amino acid sequence of KKKKKKP (SEQ ID NO: 3) or DKDD (SEQ ID NO: 7). In cases in which one or more of the additional elements described herein are present on or in the peptide of the invention, the one or more elements can be attached to or placed within the peptide of the invention by means of a spacer. Such a spacer is preferably a proline (P), glycine (G), serine (S) or glycine-serine (GS) spacer well known in the art. A particularly preferred spacer of this group is a glycine-glycine (GG) spacer or a proline-proline (PP) spacer. According to a preferred embodiment, the peptide of the present invention comprises a cardiomyocyte-targeting peptide tag as described herein (preferably having SEQ ID NO: 2) connected via a spacer (preferably a glycine-glycine (GG) spacer) to the peptide of the invention. Accordingly, a particularly preferred variant of the peptide of the present invention has the amino acid sequence of KKKKKKP-GG-YVVLVAALTVACNNFFWENS (SEQ ID NO: 4). According to an alternative preferred embodiment, the peptide of the present invention comprises a peptide tag as described herein (preferably having SEQ ID NO: 7) connected via a spacer (preferably a proline-proline (PP) spacer) to the peptide of the invention. Accordingly, a particularly preferred variant of the peptide of the present invention has the amino acid sequence of DKDD-PP- YVVLVAALTVACNNFFWENS (SEQ ID NO: 8). It will be appreciated that any tag and / or spacer sequences attached to the peptide of the invention do not hamper the biological activity of the peptide, as shown in the examples section below.

[0128] According to a further preferred embodiment, the peptide does not comprise any amino acid sequence of the human S100A protein N- and / or C-terminally of the amino acid sequence according to SEQ ID NO: 1. The human S100A protein has the sequence as shown in SEQ ID NO: 5. The peptide in accordance with the present invention is based on a fragment of human S100A protein and is thus comprised within the sequence of SEQ ID NO: 5. Therefore, the expression “the peptide does not comprise any amino acid sequence of the human S100A protein N- and / or C- terminally of the amino acid sequence according to SEQ ID NO: 1” means that the peptide in accordance with the present invention does not comprise one or more additional amino acids in the order as shown in amino acid sequence SEQ ID NO: 5, which amino acids are located N-terminally of the sequence of SEQ ID NO: 1 or C-terminally of the sequence of SEQ ID NO: 1. For example, as shown for SEQ ID NO: 5 above, in which SEQ ID NO: 1 is underlined, the peptide in accordance with this embodiment of the present invention does not comprise a glutamic acid (E) in the first position N-terminally of SEQ ID NO: 1. Likewise, the peptide in accordance with this embodiment of the present invention does not comprise e.g. QE in the first two positions C- terminally of SEQ ID NO: 1, FQE in the first three positions N-terminally of SEQ ID NO: 1, DFQE in the first four positions C-terminally of SEQ ID NO: 1 and so on when referring to SEQ ID NO: 5.

[0129] In the experiments leading to the present invention, it was surprisingly found that the peptide in accordance with the invention is by itself cell-permeable and does not require any additional permeation enhancers such as permeation enhancing peptide domains. Accordingly, according to a preferred embodiment, the peptide in accordance with the invention does not comprise any membrane penetration enhancing domain. The term “membrane penetration enhancing domain” as used herein includes specific peptide domains that enable the transition of a peptide or protein through a cell membrane. Non-limiting examples of membrane penetration enhancing domains include the human immuno-deficiency virus- Transcription-transactivating) peptide (Nagahara et al. Nature medicine. 1998; 4(12): 1449; Fischer et al. Bioconjugate chemistry. 2001; 12 (6): 825-41), and the cell-penetrating HIV-TAT peptide as disclosed e.g. in Dowarha et al. 2020.

[0130] According to a specific embodiment, the peptide in accordance with the invention consists of between 11 and 40 amino acids, such as between 12 and 39 amino acids, between 13 and 38 amino acids, between 14 and 37 amino acids, between 15 and 36 amino acids, between 16 and 35 amino acids, between 17 and 34 amino acids, between 18 and 35 amino acids, between 19 and 34 amino acids, between 20 and 33 amino acids, between 21 and 32 amino acids, between 22 and 31 amino acids, between 23 and 30 amino acids, between 24 and 29 amino acids, between 25 and 28 amino acids, or between 26 and 28 amino acids.

[0131] The present invention further provides a nucleic acid encoding the peptide, fragment or variant thereof in accordance with the invention. The nucleic acid can be used in the treatment of cancer, or in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF) as disclosed herein. In embodiments of the present invention, the nucleic acid encoding the peptide, fragment or variant thereof in accordance with the invention is comprised in a vector. Preferably, the vector is selected from the group consisting of plasmid vectors, cosmid vectors, phage vectors such as lambda phage, filamentous phage vectors, viral vectors, viral like particles, and bacterial spores. It is particularly preferred that the viral vector is selected from the group consisting of an adenoviral vector, adeno- associated viral (AAV) vector, alphaviral vector, herpes viral vector, measles viral vector, pox viral vector, vesicular stomatitis viral vector, retroviral vector and lentiviral vector. In preferred embodiments, the vector integrates into the genome, preferably into the genome of myocardial cells. In further preferred embodiments, the vector is an AAV selected from the group consisting of AAV5, AAV6 and AAV9. These vectors can be used in in the treatment of cancer, or in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction CTRCD and CTRHF.

[0132] In preferred embodiments, the above described vector triggers the expression of the peptide or of the fragment or variant thereof in cells, preferably in myocardial cells. In further preferred embodiments, the expression of the peptide, fragment or variant is controlled by a heart tissue specific promoter. Thus, according to a preferred embodiment, the vector further comprises a heart tissue specific promoter. Preferably the heart tissue specific promoter is selected from the group consisting of but not limited to Cardiac Actin Enhancer / Elongation Factor 1 promoter, Cytomegalo-virus enhancer / Myosin light chain ventricle 2 promoter and Troponin. The vector in accordance with the present invention can be used in the treatment of cancer, or in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent- mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF) as disclosed herein. Thus, according to one aspect, the present invention provides an expression vector comprising the nucleic acid of the invention for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF), preferably wherein the nucleic acid is operably linked to a control sequence.

[0133] According to a preferred embodiment, the nucleic acid is operably linked to a control sequence.

[0134] According to a further aspect, the present invention provides a recombinant host cell or culture of recombinant host cells comprising the nucleic acid of the invention or the expression vector of the invention for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF) as disclosed herein.

[0135] According to a further aspect, the present invention provides a pharmaceutical composition comprising the peptide of the invention, the nucleic acid of the invention, the expression vector of the invention, or the host cell or culture of host cells of the invention, and a pharmaceutically acceptable excipient for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF) as disclosed herein.

[0136] According to a further aspect, the present invention provides a pharmaceutical composition comprising a combination of the peptide of the present invention and at least one antineoplastic agent. According to a preferred embodiment, the pharmaceutical composition is for use in treating cancer. According to a further preferred embodiment, the antineoplastic agent is selected from doxorubicin and / or sunitinib. Thus, the present invention also provides a combination therapy for treating cancer comprising the peptide of the present invention and an antineoplastic agent.

[0137] According to one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the peptide or its fragment or variant as described herein, of the nucleic acid, or of the vector of the present invention, which are herein also referred to as the “active ingredient”. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient, preferably in purified form, together with a suitable amount of a carrier and / or excipient so as to provide the form for proper administration to the patient. The formulation of the composition should suit the mode of administration. For intravenous administration, it is preferred that the carrier is an aqueous carrier. According to one embodiment, such an aqueous carrier is capable of imparting improved properties when combined with an antigen binding polypeptide of the invention, for example, improved solubility, efficacy, and / or improved immunotherapy.

[0138] According to one embodiment, the pharmaceutical composition may comprise a further therapeutic agent or pharmacologically active substance such as but not limited to adjuvants and / or additional active ingredients, in a pharmaceutically or physiologically acceptable formulation selected to be suitably administered according to the selected mode of administration.

[0139] According to one embodiment, the pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. For preparing pharmaceutical compositions of the present invention, pharmaceutically acceptable carriers can be either solid or liquid and are preferably liquid. Liquid form compositions include solutions, suspensions, and emulsions, for example, water, saline solutions, aqueous dextrose, glycerol solutions or water / propylene glycol solutions. For parenteral injections (e.g. intravenous, intra-arterial, intraosseous infusion, intramuscular, subcutaneous, intraperitoneal, intradermal, and intrathecal injections), liquid preparations can be formulated in solution in, e.g. aqueous polyethylene glycol solution. A saline solution is a preferred carrier when the pharmaceutical composition is to be administered intravenously.

[0140] According to one embodiment, the pharmaceutical composition is in a unit dosage form. In such form, the composition may be subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, the package containing discrete quantities of the composition, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, an injection vial, a tablet, a cachet, or a lozenge itself, or it can be the appropriate number of any of these in packaged form. The pharmaceutical composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0141] The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and gender of the patient, the desired duration of the treatment etc. The pharmaceutical composition may be in any suitable form depending on the desired method of administering it to a patient.

[0142] According to one embodiment, the pharmaceutical composition comprises vehicles, which are pharmaceutically acceptable for a formulation capable of being injected into a patient. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts) or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.

[0143] To prepare pharmaceutical compositions, an effective amount of the active ingredient may be dissolved or dispersed in a pharmaceutically acceptable carrier or in an aqueous medium. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions of the active compounds in the form of a free base or of pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0144] According to one embodiment, the peptide or its fragment or variant described herein, the nucleic acid, or the vector of the present invention can be formulated into a pharmaceutical composition in a neutral or salt form using pharmaceutically acceptable salts.

[0145] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by fdtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-fdtered solution thereof.

[0146] According to a preferred embodiment, the pharmaceutical composition is administered through the oral, intravenous, intramucosal, intraarterial, intramuscular or intracoronal route. Intravenous administration is preferred.

[0147] In preferred embodiments, administration of the protein, the biologically active fragment thereof, the nucleic acid, the vector or the pharmaceutical composition of the present invention results in an increase in the concentration of the peptide in the myocardium of said individual.

[0148] According to a further aspect, the present invention provides the nucleic acid of the invention, the expression vector of the invention, the host cell or culture of host cells of the invention, or the pharmaceutical composition of the invention, wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, (osteo)sarcoma, lymphoma, leukemia, myeloma, thyroid cancer, gastric cancer, colon cancer, and pancreas cancer.

[0149] According to an embodiment, the antineoplastic agent-mediated cytotoxicity is anthracycline-mediated cytotoxicity.

[0150] According to a further embodiment, the anthracycline-mediated cytotoxicity is doxorubicin-mediated cytotoxicity. According to a preferred embodiment, the peptide, the nucleic acid or set of nucleic acids, the expression vector, the host cell or culture of host cells, or the pharmaceutical composition is administered prior to or during an antineoplastic treatment.

[0151] According to a further embodiment, the present invention provides the peptide or the pharmaceutical composition of the invention for use in reducing the use such as the amount or dose of one or more cytostatic drugs during cancer treatment, comprising administering to a patient undergoing cancer therapy or who is about to undergo cancer therapy a therapeutically effective amount of the peptide or of the pharmaceutical composition of the invention, wherein the cancer therapy includes administering to the patient one or more cytostatic drugs. According to one embodiment, the reduction is about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10- fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold or higher reduction in the dose of the cytostatic drug, preferably in the dose of doxorubicin or sunitinib. Preferably the reduction is about 10-fold.

[0152] According to a further aspect, the present invention provides a method of treating cancer in a subject in need thereof, wherein the method comprises the step of administering to the subject a therapeutically effective amount of the peptide of the invention.

[0153] According to a further aspect, the present invention provides a method of treating or preventing antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy- related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF) in a subject in need thereof, wherein the method comprises the step of administering to the subject a therapeutically effective amount of the peptide of the invention.

[0154] According to a preferred embodiment, the patient has received or is receiving therapy with an antineoplastic agent, preferably an anthracycline, more preferably doxorubicin.

[0155] According to a further embodiment, the present invention provides a method of reducing the use such as the amount or dose of one or more cytostatic drugs during cancer treatment, the method comprising the step of administering to a patient undergoing cancer therapy or who is about to undergo cancer therapy a therapeutically effective amount of the peptide or of the pharmaceutical composition of the invention, wherein the cancer therapy includes administering to the patient one or more cytostatic drugs. According to one embodiment, the reduction is about 2- fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold or higher reduction in the dose of the cytostatic drug, preferably in the dose of doxorubicin or sunitinib. Preferably the reduction is about 10-fold.

[0156] The present invention further provides the use of the peptide of the invention, the nucleic acid of the invention, the expression vector of the invention, or the host cell or culture of host cells of the invention for the preparation of a medicament. According to one embodiment, the medicament is for treating cancer, or for the treatment or prevention of antineoplastic agent- mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF). According to a preferred embodiment, the medicament is for treating or preventing cancer, more preferably for treating or preventing breast cancer, cervical cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, (osteo)sarcoma, lymphoma, leukemia, myeloma, thyroid cancer, gastric and colon cancer and pancreas cancer.

[0157] The present invention further relates to the following items:

[0158] Item 1 : A peptide comprising or consisting of

[0159] (i) the amino acid sequence YVVLVAALTVACNNFFWENS (SEQ ID NO: 1),

[0160] (ii) a fragment of the amino acid sequence according to SEQ ID NO: 1, wherein between 1 and 9 amino acids are deleted at the N-terminus of SEQ ID NO: 1, or

[0161] (iii) a variant of (i) or (ii) having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or fragment thereof, for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

[0162] Item 2: The peptide for use according to item 1, further comprising one or more elements independently selected from the group consisting of a hydrophilic domain, an epitope-tag and a targeting domain, preferably wherein the peptide does not comprise a membrane penetration enhancing domain.

[0163] Item 3: The peptide for use according to item 1 or 2, wherein the peptide consists of between 11 and 40 amino acids and wherein the peptide preferably does not comprise any amino acid sequence of a human S100A protein N- and C-terminally of the amino acid sequence according to SEQ ID NO: 1.

[0164] Item 4: A nucleic acid encoding the peptide as defined in any one of items 1 to 3 for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

[0165] Item 5 : An expression vector comprising the nucleic acid as defined in item 4 for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF), preferably wherein the nucleic acid is operably linked to a control sequence.

[0166] Item 6: A recombinant host cell or culture of recombinant host cells comprising the nucleic acid as defined in item 4 or the expression vector as defined in item 5 for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy- related heart failure (CTRHF).

[0167] Item 7: A pharmaceutical composition comprising the peptide as defined in any one of items 1 to 3, the nucleic acid as defined in item 4, the expression vector as defined in item 5, or the host cell or culture of host cells as defined in item 6, and a pharmaceutically acceptable excipient for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent- mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

[0168] Item 8: The peptide for use according to any one of items 1 to 3, the nucleic acid for use according to item 4, the expression vector for use according to item 5, the host cell or culture of host cells for use according to item 6, or the pharmaceutical composition for use according to item 7, wherein the cancer is breast cancer, cervical cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, (osteo)sarcoma, lymphoma, leukemia, myeloma, thyroid cancer, gastric and colon cancer and pancreas cancer.

[0169] Item 9: The peptide for use according to any one of items 1 to 3, the nucleic acid for use according to item 4, the expression vector for use according to item 5, the host cell or culture of host cells for use according to item 6, or the pharmaceutical composition for use according to item 7, wherein the antineoplastic agent-mediated cytotoxicity is anthracycline-mediated cytotoxicity.

[0170] Item 10: The peptide for use according to any one of items 1 to 3, the nucleic acid for use according to item4, the expression vector for use according to item5, the host cell or culture of host cells for use according to item6, or the pharmaceutical composition for use according to item 7, wherein the anthracycline-mediated cytotoxicity is doxorubicin-mediated cytotoxicity.

[0171] Item 11: The peptide, the nucleic acid, the expression vector, the host cell or culture of host cells, or the pharmaceutical composition for use according to any one of items 1 to 10, wherein the peptide, the nucleic acid or set of nucleic acids, the expression vector, the host cell or culture of host cells, or the pharmaceutical composition is administered prior to or during an antineoplastic treatment.

[0172] Item 12: A pharmaceutical composition comprising a combination of comprising the peptide as defined in any one of items 1 to 3, the nucleic acid as defined in item 4, the expression vector as defined in item 5, or the host cell or culture of host cells as defined in item 6, and at least one antineoplastic agent, preferably wherein the pharmaceutical composition is for use in treating cancer.

[0173] Item 13: Method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide as defined in any of items 1 to 3, the nucleic acid as defined in item 4, the expression vector as defined in item 5, the host cell or culture of host cells as defined in item 6 or the pharmaceutical composition as defined in item 12.

[0174] Item 14: Method of treating or preventing antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy- related heart failure (CTRHF) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide as defined in any of items 1 to 3, the nucleic acid as defined in item 4, the expression vector as defined in item 5, the host cell or culture of host cells as defined in item 6 or the pharmaceutical composition as defined in item 12. Item 15: The method of item 13 or 14, wherein the patient has received or is receiving therapy with an antineoplastic agent, preferably an anthracycline, more preferably doxorubicin.

[0175] EXAMPLES

[0176] The Examples are designed to further illustrate the present invention and to serve a better understanding. They are not to be construed as limiting the scope of the invention in any way.

[0177] Example 1

[0178] SlOOAlct protects against doxorubicin-mediated cytotoxicity

[0179] SlOOAlct shows a significant protective effect against doxorubicin- and sunitinib-mediated cytotoxicity. 10,000 nM of SlOOAlct peptide (SEQ ID NO: 8) and 100 nM doxorubicin or 1,000 nM sunitinib were co-incubated for 24 hours with neonatal rat cardiac myocytes. Cardiac myocyte damage was assessed using the commercial high-throughput Toxilight Cytotoxicity BioAssay (Lonza; with CellTiter 96® Non-Radioactive Cell Proliferation Assay, Promega) which detects and quantifies necrosis-induced adenylate kinase (AK) release into supernatants of medium (M199 medium supplemented with 1% penicillin / streptomycin and 0.5% FBS).

[0180] Fig. 1 shows the fold-change in necrosis-induced adenylate kinase release in response to treatments with vehicle alone (untreated), doxorubicin or sunitinib alone, and in combination with SlOOAlct. This experiment shows that the SlOOAlct peptide of the invention exhibits a direct cardioprotective effect against doxorubicin-mediated cardiomyocyte damage (Fig. 1A) and sunitinib-mediated cardiomyocyte damage (Fig. IB) in vitro.

[0181] Example 2

[0182] Oncolytic activity of the SlOOAlct peptide

[0183] SlOOAlct (produced as described in Example 1) shows a strong oncolytic activity against selected human cancer cell lines (Figs. 2 and 3). As shown in Fig. 2A, SlOOAlct peptide has a dose-dependent, significant oncolytic effect on cervical (Hela) and breast epithelial carcinoma cells (MCF7), which is demonstrated by a significant reduction in the number of proliferating Hela and MCF7 cancer cells (Fig. 2B). The equivalent oncolytic potency of SlOOAlct (1,000 nM) on cervical carcinoma cells (Hela) as an example compared to the anthracycline doxorubicin (100 nM) and the tyrosine kinase inhibitor sunitinib (1,000 nM) is shown in Fig. 2C.

[0184] SlOOAlct does not exert any cytotoxic effect on normal mammalian cells such as MEF or COS1 cells (Figs. 2D and E).

[0185] Cytotoxicity and cell numbers were assessed using the commercial high-throughput CellTiter-Glo Cell Viability and MTT Cell proliferation assays, respectively. Assays were performed 24 hours after S100A let, doxorubicin and sunitinib incubation. Fig. 3 shows the synergistic oncolytic activity of SlOOAlct with doxorubicin or sunitinib on cancer cells. Fig. 3A shows the oncolytic effect of SlOOAlct (1 pM) in combination with 10 nM doxorubicin on cancer cells. This effect is as strong as that of the 10-fold higher dose of doxorubicin (100 nM) alone. SlOOAlct (1 pM) thus enables a reduction in the cardiotoxic effect of doxorubicin while maintaining an overall oncolytic effect of the same strength. Fig. 3B shows the oncolytic effect of SlOOAlct (1 pM) in combination with 100 nM sunitinib on cancer cells, which is as strong as that of the 10-fold higher dose of sunitinib (1000 nM) alone. SlOOAlct thus enables a reduction in the cardiotoxic effect of sunitinib while maintaining an overall oncolytic effect of the same strength.

[0186] Example 3

[0187] SlOOAlct protects against high concentrations of cytotoxic drugs

[0188] Cultured non-refractory cardiomyocytes (NRCM) were treated for 24 hours in a petri-dish with the SlOOAlct peptide alone (10 pM) or with a combination of SlOOAlct peptide (10 pM) + doxorubicin (500 nM) or sunitinib (10 pM). Supernatant was collected after 24 hours. Adenylate kinase (AK) content in the supernatant was determined by Toxilight Cytotoxicity BioAssay. AK release correlates directly with cell death. Results are shown in Fig. 4. This experiment shows that the SlOOAlct peptide provides a significant protective effect against doxorubicin- and sunitinib- mediated cytotoxicity even at 5- and 10-times higher concentrations of the cytostatic drug than used in Example 1.

[0189] Example 4

[0190] SlOOAlct uptake in muscle and tumor cells

[0191] Cultured non-refractory cardiomyocytes (NRCM) (n = 9 trials) and MCF7 tumor cells (n = 3 trials) were treated with 1, 10, 100 and 1000 nM of either the SlOOAlct peptide or the TAT- S100A1 as described in Dowarha et al. (PLoS ONE 2020; 15(6): e0234152). Cells were incubated in the presence of each FITC-marked peptide in a culture dish for 3 hours. After incubation, cells were washed and lysed, allowing the uptake of the peptide to be measured using fluorescence optical imaging of the attached FITC fluorescent dye using a plate reader. Dowarha et al. report that the HIV-TAT peptide sequence is required for uptake of the SlOOAlct peptide into cells. In contrast thereto and as shown in Figs. 5A and 5B, the SlOOAlct peptide does not require any membrane penetration enhancing domain such as the TAT peptide for entering the cells. The data further show that the SlOOAlct peptide (without TAT) is absorbed significantly more effectively by both cell types than the TAT-peptide. This data implies that a more effective protective effect is achieved with the same peptide quantity, leading to lower doses of the SlOOAlct peptide for achieving the same level of protection.

Claims

CLAIMS1. A peptide comprising or consisting of(i) the amino acid sequence YVVLVAALTVACNNFFWENS (SEQ ID NO: 1),(ii) a fragment of the amino acid sequence according to SEQ ID NO: 1, wherein between 1 and 9 amino acids are deleted at the N-terminus of SEQ ID NO: 1, or(iii) a variant of (i) or (ii) having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 1 or fragment thereof, for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

2. The peptide for use according to claim 1, further comprising one or more elements independently selected from the group consisting of a hydrophilic domain, an epitope-tag and a targeting domain, preferably wherein the peptide does not comprise a membrane penetration enhancing domain.

3. The peptide for use according to claim 1 or 2, wherein the peptide consists of between 11 and 40 amino acids and wherein the peptide preferably does not comprise any amino acid sequence of a human S100A protein N- and C-terminally of the amino acid sequence according to SEQ ID NO: 1.

4. A nucleic acid encoding the peptide as defined in any one of claims 1 to 3 for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

5. An expression vector comprising the nucleic acid as defined in claim 4 for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF), preferably wherein the nucleic acid is operably linked to a control sequence.

6. A recombinant host cell or culture of recombinant host cells comprising the nucleic acid as defined in claim 4 or the expression vector as defined in claim 5 for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

277. A pharmaceutical composition comprising the peptide as defined in any one of claims 1 to 3, the nucleic acid as defined in claim 4, the expression vector as defined in claim 5, or the host cell or culture of host cells as defined in claim 6, and a pharmaceutically acceptable excipient for use in the treatment of cancer, or for use in the treatment or prevention of antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF).

8. The peptide for use according to any one of claims 1 to 3, the nucleic acid for use according to claim 4, the expression vector for use according to claim 5, the host cell or culture of host cells for use according to claim 6, or the pharmaceutical composition for use according to claim 7, wherein the cancer is breast cancer, cervical cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, (osteo)sarcoma, lymphoma, leukemia, myeloma, thyroid cancer, gastric and colon cancer and pancreas cancer.

9. The peptide for use according to any one of claims 1 to 3, the nucleic acid for use according to claim 4, the expression vector for use according to claim 5, the host cell or culture of host cells for use according to claim 6, or the pharmaceutical composition for use according to claim 7, wherein the antineoplastic agent-mediated cytotoxicity is anthracycline-mediated cytotoxicity.

10. The peptide for use according to any one of claims 1 to 3, the nucleic acid for use according to claim 4, the expression vector for use according to claim 5, the host cell or culture of host cells for use according to claim 6, or the pharmaceutical composition for use according to claim 7, wherein the anthracycline-mediated cytotoxicity is doxorubicin-mediated cytotoxicity.

11. The peptide, the nucleic acid, the expression vector, the host cell or culture of host cells, or the pharmaceutical composition for use according to any one of claims 1 to 10, wherein the peptide, the nucleic acid or set of nucleic acids, the expression vector, the host cell or culture of host cells, or the pharmaceutical composition is administered prior to or during an antineoplastic treatment.

12. A pharmaceutical composition comprising a combination of the peptide as defined in any one of claims 1 to 3 and at least one antineoplastic agent, preferably wherein the pharmaceutical composition is for use in treating cancer.

13. Method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide as defined in any of claims 1 to 3.

14. Method of treating or preventing antineoplastic agent-mediated cytotoxicity against cardiomyocytes or cancer therapy-related cardiac dysfunction (CTRCD) or cancer therapy-related heart failure (CTRHF) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide as defined in any of claims 1 to 3.

15. The method of claim 13 or 14, wherein the patient has received or is receiving therapy with an antineoplastic agent, preferably an anthracycline, more preferably doxorubicin.

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