Peptides for cancer therapy

Abstract

Disclosed is a peptide comprising a variant of the amino-acid sequence IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1), wherein the peptide is cytotoxic to a glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro, and wherein the peptide has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)), and wherein the amino acid sequence comprises 1-8 amino acid substitutions independently selected from: substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group or by P, and substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 12, by another amino acid selected from said group or by any one of L, I, V, F, A, W and V or by P. This peptide is suitable for prevention or treatment of a cancer, in particular glioblastoma or sarcoma.

Description

[0001]Peptides for cancer therapy The field of the present invention relates to anticancer peptides. Cancer is a major global health issue, affecting millions of people every year. While significant progress has been made in cancer treatment in recent decades, it remains a leading cause of death. Currently, surgery, chemotherapy, radiation, hormone therapy, targeted therapy and immunotherapy are standard treatments for cancer, but challenges remain. In particular, these treatments can be limited by resistance and can have a range of potential side effects due to their lack of specificity for tumor cells. Therefore, finding and developing specific antitumor drugs is a major focus of cancer research. Host defense peptides are part of the innate immune system of many diverse species (e.g. mammals, insects, amphibians). They were initially discovered due to their antimicrobial activity. Examples for antimicrobial peptides are disclosed in WO 2004 / 067563 A1 and WO 2008 / 002165 A1, as well as in Chen et al, 2021. Further examples are disclosed in WO 2014 / 182172 A1 and WO 2015 / 088344 A1. More recently, host defense peptides have emerged as potential alternative anticancer therapeutics (Mader et al., 2006). For instance, WO 2014 / 108475 A1 discloses peptides derived from host defense peptides for the treatment of cancer. The use of antimicrobial peptides as anticancer peptides is also reviewed in Felicio et al., 2017, and in Gaspar et al., 2013. Anticancer peptides are unique molecules when compared to the classical chemotherapeutic arsenal available for cancer treatment and display a variety of modes of action which in some types of cancers seem to co-exist. However, the development of selective anticancer peptides has turned out to be challenging. A constant concern when repurposing host defense peptides for cancer therapy is their hemolytic activity and off-target cytotoxicity (i.e. cytotoxicity towards non-cancerous or healthy cells in the body of the patient), especially at the doses and treatment durations required for cancer therapy. It is thus an object of the present invention to provide peptides derived from host defense peptides with anticancer or antitumor activity, in particular with reduced off-target cytotoxicity and / or reduced hemolytic activity (which in turn leads to a reduction of undesirable side effects in the patient when undergoing cancer therapy with the peptide). The present invention provides a peptide comprising a variant of the amino-acid sequence IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1). This peptide is preferably cytotoxic to a glioblastoma cell line (in particular glioblastoma cell line LN- 229) at a concentration of 20 µM in presence of human serum in vitro and / or has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)), preferably at least 10% lower, more preferably at least 20% lower, even more preferably at least 30% lower, yet even more preferably at least 40% lower, especially at least 50% lower (e.g. at 1 µM or 10 µM or 20 µM or 50 µM). The amino acid sequence of the peptide comprises 1-8 amino acid substitutions independently selected from: substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group (or by P), and substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 12 (in other words, K at position 12 remains unchanged in all variants), by another amino acid selected from said group or by any one of L, I, V, F, A, W and V, preferably L, W and V (or by P). Preferably, this peptide comprises only 7 of these amino acid substitutions, preferably only 6 of these amino acid substitutions, more preferably only 5 of these amino acid substitutions, even more preferably only 4 of these amino acid substitutions, still more preferably only 3 of these amino acid substitutions, yet more preferably only 2 of these amino acid substitutions, even more preferably only 1 of these amino acid substitutions. This peptide is preferably for use in prevention or treatment of a cancer. A highly preferred variant sequence is IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7(SEQ ID NO: 7), wherein each of X1, X2, X3, X4, X5, X6, and X7is an amino acid independently selected from the group consisting of E, K, R, L, I, V, F, A, W, V and P, preferably from the group consisting of E, K, R, L, I, V, F, A, W and V, more preferably from the group consisting of E, K, R, L, W and V (with the proviso that the sequence is not IGKEFKRIVERKKRFLRELVRPLR). Optionally, one further amino acid in the sequence IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7selected from the group of L, V, F, A, I, W, Y or Q (with the exception of X1-X7) is replaced by another amino acid selected from said group or by P (also with the proviso that the sequence is not IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1)). In embodiments, the variant has a sequence selected from the group consisting of IGKEFKRIVERKWRFLRELVRPLR (SEQ ID NO: 2), IGKKFKRIVRRKKRFLRKLVRPLR (SEQ ID NO: 3), IGKEFKRIVERKWRFLRKLVRPLR (SEQ ID NO: 4), IGKEFLRIVERKWRFLRKLVRPLL (SEQ ID NO: 5) and IGKEFLRIVERKWRFLVKLVRPLL (SEQ ID NO: 6). In addition, the present invention also provides a peptide comprising the amino-acid sequence IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1) for use in prevention or treatment of a cancer. The above-mentioned peptides may have a length of up to 100 amino acids. However, shorter lengths are preferred, preferably less than 75 amino acids, more preferably less than 50 amino acids, even more preferably less than 40 amino acids, yet even more preferably less than 35 amino acids, especially less than 30 amino acids or even less than 27 amino acids. According to a particular preference, the entire amino acid sequence of the peptide consists of said amino-acid sequence or said variant of the amino acid sequence. Furthermore, the present invention provides a peptide which is a fragment of the above-mentioned peptides (IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1) and variants thereof). This fragment comprises at least the amino-acid sequence KRIVERKKRFLR (SEQ ID NO: 93), preferably KRIVERKKRFLREL (SEQ ID NO: 58), optionally having 1-6 amino acid substitutions selected from: independently selected from: substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group or by P, and substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 7, by another amino acid selected from said group or by any one of L, I, V, F, A, W and V, preferably L, W and V, or by P. Preferably, this fragment comprises only 5 amino acid substitutions, more preferably only 4 amino acid substitutions, even more preferably only 3 amino acid substitutions, still more preferably only 2 amino acid substitutions, and especially only 1 amino acid substitution. The fragment is preferably cytotoxic to a glioblastoma cell line (in particular glioblastoma cell line LN-229) at a concentration of 20 µM in presence of human serum in vitro and / or has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)), preferably at least 10% lower, more preferably at least 20% lower, even more preferably at least 30% lower, yet even more preferably at least 40% lower, especially at least 50% lower. This fragment is preferably for use in prevention or treatment of a cancer. Preferably, the fragment comprises at least 15, preferably at least 16 or even at least 17, more preferably at least 18 or even at least 19, even more preferably at least 20 or even at least 21, yet even more preferably at least 22, especially 23 consecutive amino acids of one of above-mentioned peptides (IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1) and variants thereof as defined above). Preferably, the fragment is selected from: KRIVERKKRFLREL (SEQ ID NO: 58), KRIVERKKRFLRELV (SEQ ID NO: 59), KRIVERKKRFLRELVR (SEQ ID NO: 60), KRIVERKKRFLRELVRP (SEQ ID NO: 61), KRIVERKKRFLRELVRPL (SEQ ID NO: 62), KRIVERKKRFLRELVRPLR (SEQ ID NO: 63), FKRIVERKKRFLREL (SEQ ID NO: 64), FKRIVERKKRFLRELV (SEQ ID NO: 65), FKRIVERKKRFLRELVR (SEQ ID NO: 66), FKRIVERKKRFLRELVRP (SEQ ID NO: 67), FKRIVERKKRFLRELVRPL (SEQ ID NO: 68), FKRIVERKKRFLRELVRPLR (SEQ ID NO: 69), EFKRIVERKKRFLREL (SEQ ID NO: 70), EFKRIVERKKRFLRELV (SEQ ID NO: 71), EFKRIVERKKRFLRELVR (SEQ ID NO: 72), EFKRIVERKKRFLRELVRP (SEQ ID NO: 73), EFKRIVERKKRFLRELVRPL (SEQ ID NO: 74), EFKRIVERKKRFLRELVRPLR (SEQ ID NO: 75), KEFKRIVERKKRFLREL (SEQ ID NO: 76), KEFKRIVERKKRFLRELV (SEQ ID NO: 77), KEFKRIVERKKRFLRELVR (SEQ ID NO: 78), KEFKRIVERKKRFLRELVRP (SEQ ID NO: 79), KEFKRIVERKKRFLRELVRPL (SEQ ID NO: 80), KEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 81), GKEFKRIVERKKRFLREL (SEQ ID NO: 82), GKEFKRIVERKKRFLRELV (SEQ ID NO: 83), GKEFKRIVERKKRFLRELVR (SEQ ID NO: 84), GKEFKRIVERKKRFLRELVRP (SEQ ID NO: 85), GKEFKRIVERKKRFLRELVRPL (SEQ ID NO: 86), GKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 87), IGKEFKRIVERKKRFLREL (SEQ ID NO: 88), IGKEFKRIVERKKRFLRELV (SEQ ID NO: 89), IGKEFKRIVERKKRFLRELVR (SEQ ID NO: 90), IGKEFKRIVERKKRFLRELVRP (SEQ ID NO: 91), IGKEFKRIVERKKRFLRELVRPL (SEQ ID NO: 92), and variants thereof optionally having 1-6 amino acid substitutions independently selected from: substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group or by P, and substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 7, by another amino acid selected from said group or by any one of L, I, V, F, A, W and V or by P; wherein the fragment is cytotoxic to a glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro and wherein the fragment has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl-IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)); preferably for use in prevention or treatment of a cancer. Preferably, this fragment comprises only 5 of these amino acid substitutions, even more preferably only 4 of these amino acid substitutions, still more preferably only 3 of these amino acid substitutions, yet more preferably only 2 of these amino acid substitutions, even more preferably only 1 of these amino acid substitutions. According to further embodiments, the length of the fragment peptide is 12-23 amino acids, preferably 13-22 amino acids or even 14-21 amino acids, more preferably 14-20 amino acids or even 14-19 amino acids, even more preferably 14-18 amino acids or even 14-17 amino acids, yet even more preferably 14-16 amino acids or even 14-15 amino acids, especially 14 amino acids. Another aspect of the present invention relates to a method (for the treatment or delay of onset of a cancer), comprising obtaining a pharmaceutical composition comprising the peptide as defined herein, and administering the pharmaceutical composition to an individual, wherein the individual has a cancer, preferably selected from the group consisting of brain cancers such as glioblastomas, breast cancers, colon cancers, esophageal cancers, prostate cancers, bladder cancer, kidney cancers, endometrial cancers, thyroid cancers, gastric cancers, liver cancers, lung cancers, pancreatic cancers, uterine cancers, tracheal cancers, testicular cancers, cervical cancers, head and neck cancers, skin cancers, bone cancers, pancreatic cancers, sarcomas, and ovarian cancers, in particular glioblastomas and sarcomas, or is at risk of developing the cancer. Short antimicrobial peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50); also called P60.4Ac) is derived from the human cathelicidin LL-37 (see Haisma et al., 2014, Piktel et al, 2016, Kuroda et al, 2015, Weber et al, 2009, and de Breij et al., 2016). In the course of the present invention, it was found that peptides derived from OP-145 with an I12K mutation (OP-145I12K) and variants thereof (as well as fragments thereof) surprisingly exhibited reduced off- target toxicity and reduced hemolytic activity while maintaining their cytotoxic effect towards cancer cell lines such as the glioblastoma cell line LN-229. This makes them exceptionally well suited as anticancer peptides, in particular for the prevention or treatment of hematologic malignancies, glioblastoma and sarcoma. Unrelated to cancer therapy, the sequence of OP-145I12Kwas published in Ön, 2017, and Piller, 2019. These documents were focused on the antimicrobial properties of OP-145I12K. In the course of the present invention, a consensus sequence was found which is particularly suitable for anticancer peptides. As mentioned above, this consensus sequence is IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7(SEQ ID NO: 7).The peptide of the present invention preferably comprises this sequence, with X1to X7being further defined as above. Optionally, one amino acid in the sequence IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7(SEQ ID NO: 7) selected from the group of L, V, F, A, I, W, Y or Q, with theexception of X1-X7, is replaced by another amino acid selectedfrom said group or by P. According to a particular preference, X1to X7are further defined as follows: X1is E, K or R; X2is E, K, R, L, I, V, F, A, W, or V; X3is E, K or R; X4is E, K, R, L, I, V, F, A, W, or V; X5is E, K, R, L, I, V, F, A, W, or V; X6is E, K or R; and X7 is E, K, R, L, I, V, F, A, W, or V. More specifically, X1to X7are preferably defined as follows: X1is E, K or R; X2is K, L, I or V; X3is E, K or R; X4 is K, L, I, V, F, A, W, or V; X5is R, L, I or V; X6is E, K or R; and X7is R, L, I or V. Even more specifically, X1to X7are preferably defined as follows: X1is E or K; X2is K or L; X3is E or R; X4is K or W; X5is R or V; X6 is E or K; and X7is R or L. This consensus sequence is also suitable for the inventive fragment peptides. Preferably, the fragment of the fragment peptide is selected from: X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 15), X2RIVX3RKX4RFLX5X6LV (SEQ ID NO: 16), X2RIVX3RKX4RFLX5X6LVR (SEQ ID NO: 17), X2RIVX3RKX4RFLX5X6LVRP (SEQ ID NO: 18), X2RIVX3RKX4RFLX5X6LVRPL (SEQ ID NO: 19), X2RIVX3RKX4RFLX5X6LVRPLR (SEQ ID NO: 20), FX2RIVX3RKX4RFLX5X6L (SEQ ID NO: 21), FX2RIVX3RKX4RFLX5X6LV (SEQ ID NO: 22), FX2RIVX3RKX4RFLX5X6LVR (SEQ ID NO: 23), FX2RIVX3RKX4RFLX5X6LVRP (SEQ ID NO: 24), FX2RIVX3RKX4RFLX5X6LVRPL (SEQ ID NO: 25), FX2RIVX3RKX4RFLX5X6LVRPLR (SEQ ID NO: 26), EFX2RIVX3RKX4RFLX5X6L (SEQ ID NO: 27), EFX2RIVX3RKX4RFLX5X6LV (SEQ ID NO: 28), EFX2RIVX3RKX4RFLX5X6LVR (SEQ ID NO: 29), EFX2RIVX3RKX4RFLX5X6LVRP (SEQ ID NO: 30), EFX2RIVX3RKX4RFLX5X6LVRPL (SEQ ID NO: 31), EFX2RIVX3RKX4RFLX5X6LVRPLR (SEQ ID NO: 32), KEFX2RIVX3RKX4RFLX5X6L (SEQ ID NO: 33), KEFX2RIVX3RKX4RFLX5X6LV (SEQ ID NO: 34), KEFX2RIVX3RKX4RFLX5X6LVR (SEQ ID NO: 35), KEFX2RIVX3RKX4RFLX5X6LVRP (SEQ ID NO: 36), KEFX2RIVX3RKX4RFLX5X6LVRPL (SEQ ID NO: 37), KEFX2RIVX3RKX4RFLX5X6LVRPLR (SEQ ID NO: 38), GKEFX2RIVX3RKX4RFLX5X6L (SEQ ID NO: 39), GKEFX2RIVX3RKX4RFLX5X6LV (SEQ ID NO: 40), GKEFX2RIVX3RKX4RFLX5X6LVR (SEQ ID NO: 41), GKEFX2RIVX3RKX4RFLX5X6LVRP (SEQ ID NO: 42), GKEFX2RIVX3RKX4RFLX5X6LVRPL (SEQ ID NO: 43), GKEFX2RIVX3RKX4RFLX5X6LVRPLR (SEQ ID NO: 44), IGKEFX2RIVX3RKX4RFLX5X6L (SEQ ID NO: 45), IGKEFX2RIVX3RKX4RFLX5X6LV (SEQ ID NO: 46), IGKEFX2RIVX3RKX4RFLX5X6LVR (SEQ ID NO: 47), IGKEFX2RIVX3RKX4RFLX5X6LVRP (SEQ ID NO: 48), and IGKEFX2RIVX3RKX4RFLX5X6LVRPL (SEQ ID NO: 49), with X2-X6as defined above. Optionally, one amino acid in the sequence FX2RIVX3RKX4RFLX5X6L (SEQ ID NO: 21) selected from the group of L, V, F, A, I, W, Y or Q, with the exception of X2-X6, is replaced by another amino acid selected from said group or by P. In a further preferred embodiment, the fragment has the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 15), wherein: X2is E, K, R, L, I, V, F, A, W, or V; X3is E, K or R; X4is E, K, R, L, I, V, F, A, W, or V; X5is E, K, R, L, I, V, F, A, W, or V; and X6is E, K or R. More specifically, the fragment has the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 15), wherein: X2is K, L, I or V; X3 is E, K or R; X4is K, L, I, V, F, A, W, or V; X5 is R, L, I or V; and X6is E, K or R. Yet even more specifically, the fragment has the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 15), wherein: X2is K or L; X3 is E or R; X4is K or W; X5is R or V; and X6is E or K. Preferably, the fragment peptide consists of any one of the above fragment sequences. According to a particular preference, the peptide of the present invention is less cytotoxic to a (human) fibroblast cell line (e.g. primary dermal fibroblasts, normal, human, adult (HDFa); PCS-201-012 from the American Type Culture Collection, ATCC) than to the glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro. In a further preferred embodiment, the peptide is N- terminally modified, preferably with an acetyl, hexanoyl, decanoyl, myristoyl, PEGyl, propionyl or dye moiety, and / or C- terminally modified, preferably with an amide, PEGyl, amino- hexanoyl or dye moiety. In another preferred embodiment, the peptide comprises an N- terminal acetyl moiety or a C-terminal amide moiety, preferably both. It is particularly preferred that the length of the peptide is 14-50 amino acids, preferably 24-40 amino acids, in particular 24-30 amino acids. One skilled in the art can easily synthesize the peptides of the present invention upon having read the present specification. Standard procedures for preparing synthetic peptides are well known in the art. Peptides of the present invention can be synthesized by commonly used methods as t-BOC or FMOC protection, preferably FMOC protection, of alpha-amino groups. Both methods involve stepwise syntheses whereby a single amino acid is added at each step starting from the carboxyl- terminus of the peptide (See, Coligan et al., Current Protocols in Immunology, Wiley Interscience, 1991, Unit 9). Peptides of the invention can also be synthesized by the solid phase peptide synthesis methods well known in the art. (Merrifield, J. Am. Chem. Soc., 85:2149, 1963), and Stewart and Young, Solid Phase Peptides Synthesis, Pierce, Rockford, Ill. (1984)). Peptides can be synthesized using a copoly(styrene-divinylbenzene) containing 0.1-1.0 mMol amines / g polymer. On completion of chemical synthesis, the peptides can be deprotected and cleaved from the polymer by treatment with liquid HF-10% anisole for about 0.25 to 1 hour at 0°C. After evaporation of the reagents, the peptides are extracted from the polymer with 1% acetic acid solution which is then lyophilized to yield the crude material. This can typically be purified by such techniques as gel filtration on Sephadex G-15 using 5% acetic acid as a solvent, by high pressure liquid chromatography, and the like. Lyophilization of appropriate fractions of the column will yield the homogeneous peptide or peptide derivatives, which can then be characterized by such standard techniques as amino acid analysis, thin layer chromatography, high performance liquid chromatography, ultraviolet absorption spectroscopy, molar rotation, solubility, and assessed by the solid phase Edman degradation (see e.g Protein Purification, M. P. Deutscher, ed. Methods in Enzymology, Vol 182, Academic Press, 1990). Automated synthesis using FMOC solid phase synthetic methods can be achieved using an automated peptide synthesizer. Of course, it is also possible to produce the peptides of the present invention using recombinant methods. The peptides can be produced in microorganisms such as bacteria, yeast or fungi, in eukaryotic cells such as mammalian or insect cells, or in a recombinant virus vector such as adenovirus, poxvirus, herpesvirus, Simliki forest virus, baculovirus, bacteriophage, sindbis virus or sendai virus. Suitable bacteria for producing the peptides include E. coli, B. subtilis or any other bacterium that is capable of expressing such peptides. Suitable yeast cells for expressing the peptides of the present invention include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida, Pichiapastoris or any other yeast capable of expressing peptides. Corresponding means and methods are well known in the art. Also, methods for isolating and purifying recombinantly produced peptides are well known in the art and include e.g. gel filtration, affinity chromatography, ion exchange chromatography etc. To facilitate isolation of said peptides, fusion polypeptides may be made wherein the peptides are translationally fused (covalently linked) to a heterologous polypeptide which enables isolation by affinity chromatography. Typical heterologous polypeptides are His-Tag (e.g. His6; 6 histidine residues), GST-Tag (Glutathione-S-transferase) etc. The fusion polypeptide facilitates not only the purification of the peptides but can also prevent the degradation of the peptides during the purification steps. If it is desired to remove the heterologous polypeptide after purification, the fusion polypeptide may comprise a cleavage site at the junction between the peptide and the heterologous polypeptide. The cleavage site may consist of an amino acid sequence that is cleaved with an enzyme specific for the amino acid sequence at the site (e.g. proteases). The peptides of the present invention may form a salt by addition of an acid. Examples of the acid include inorganic acids (such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) or organic carboxylic acids (such as acetic acid, propionic acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, and salicylic acid), acidic sugars such as glucuronic acid, galacturonic acid, gluconic acid, ascorbic acid, etc., acidic polysaccharides such as hyaluronic acid, chondroitin sulfates, alginic acid, or organic sulfonic acids (such as methanesulfonic acid, and p-toluenesulfonic acid), and the like. Of these salts, preferred is a pharmaceutically acceptable salt. The peptides of the present invention may form a salt with a basic substance. Examples of the salt include, for example, pharmaceutically acceptable salts selected from salts with inorganic bases such as alkali metal salts (sodium salt, lithium salt, potassium salt etc.), alkaline earth metal salts, ammonium salts, and the like or salts with organic bases, such as diethanolamine salts, cyclohexylamine salts and the like. In the context of the present invention, the individual (to be treated with the peptide of the present invention) may be a human or non-human animal, preferably a non-human primate, a sheep, a pig, a dog or a rodent, in particular a mouse. According to another preferred embodiment, the cancer (to be prevented or treated) is selected from the group consisting of brain cancers such as glioblastomas, breast cancers, colon cancers, esophageal cancers, prostate cancers, bladder cancer, kidney cancers, endometrial cancers, thyroid cancers, gastric cancers, liver cancers, lung cancers, pancreatic cancers, uterine cancers, tracheal cancers, testicular cancers, cervical cancers, head and neck cancers, skin cancers, bone cancers, pancreatic cancers, sarcomas, and ovarian cancers, in particular glioblastomas and sarcomas. The cancer may be a primary cancer or a metastatic cancer. In embodiments, the cancer may be a brain cancer (e.g. glioma, glioblastoma, cerebellar brain tumors). In other embodiments, the cancer may be a hematological malignancy, in particular selected from the group of leukemias, lymphomas and multiple myelomas. In another preferred embodiment, the peptide is administered in combination with cancer immunotherapy, radiation therapy or chemotherapy. Alternatively, or in addition thereto, the peptide may be administered as a neoadjuvant therapy. Intravenous administration of the peptide is preferred. However, other modes of administration are also possible. The peptides of the present invention are preferably administered to the individual in need thereof in an amount of 100µg / kg body weight to 100mg / kg body weight, preferably 1mg / kg body weight to 50mg / kg body weight, more preferably 5mg / kg body weight to 15mg / kg body weight, in particular 10mg / kg body weight. Alternatively, or in addition thereto, the peptides of the present invention are preferably administered daily (e.g. three times a day, twice a day or once a day), every 2nd, every 3rd, every 4th, every 5th day, every 6th day or weekly. The peptide of the present invention may be provided in a pharmaceutical composition. This pharmaceutical composition is preferably provided with at least one excipient. Excipients suitable for the pharmaceutical composition of the present invention are known to the person skilled in the art, upon having read the present specification, for example water (especially water for injection), saline, Ringer's solution, dextrose solution, buffers, Hank solution, 5% dextrose in saline, substances that enhance isotonicity and chemical stability, buffers and preservatives. This pharmaceutical composition can (as a drug) be administered via appropriate procedures known to the skilled person (upon having read the present specification) to a patient or individual in need thereof (i.e. a patient or individual having or having the risk of developing the diseases or conditions mentioned herein). The preferred route of administration of said pharmaceutical composition is parenteral administration, in particular through intraperitoneal, subcutaneous, intramuscular and / or intravenous administration. The dosage and method of administration depends on the individual patient or individual to be treated. Said pharmaceutical composition can be administered in any suitable dosage known from other biological dosage regimens or specifically evaluated and optimised for a given individual. For example, the nucleic acid cargo may be present in the pharmaceutical composition in an amount from 1 mg to 10 g, preferably 50 mg to 2 g, in particular 100 mg to 1 g. Usual dosages can also be determined on the basis of kg body weight of the patient, for example preferred dosages are in the range of 0.1 mg to 100 mg / kg body weight, especially 1 to 10 mg / kg body weight (per administration session). The administration may occur e.g. once daily, once every other day, once per week or once every two weeks. As the preferred mode of administration of the inventive pharmaceutical composition is parenteral administration, the pharmaceutical composition according to the present invention is preferably liquid or ready to be dissolved in liquid such sterile, de-ionised or distilled water or sterile isotonic phosphate-buffered saline (PBS). Preferably, 1000 µg (dry-weight) of such a composition comprises 0.1-990 µg, preferably 1-900µg, more preferably 10- 200µg compound, and option-ally 1-500 µg, preferably 1-100 µg, more preferably 5-15 µg (buffer) salts (preferably to yield an isotonic buffer in the final volume), and optionally 0.1-999.9 µg, preferably 100-999.9 µg, more preferably 200-999 µg other excipients. Preferably, 100 mg of such a dry composition is dissolved in sterile, de- ionised / distilled water or sterile isotonic phosphate-buffered saline (PBS) to yield a final volume of 0.1-100 ml, preferably 0.5-20 ml, more preferably 1-10 ml. The term “preventing” or “prevention” as used herein means to stop a disease state or condition from occurring in a patient or subject completely or almost completely or at least to a (preferably significant) extent, especially when the patient or subject or individual is predisposed to such a risk of contracting a disease state or condition. As used herein, “LN-229” refers to the glioblastoma cell line LN-229 e.g. obtainable from the ATCC. The LN-229 cell line was established in 1979 from cells taken from a human patient with right frontal parieto-occipital glioblastoma (cf. Ishii et al, 1999). In the context of the present invention, the test whether a peptide at a given concentration is cytotoxic to a glioblastoma cell line (such as LN-229) in the presence of human serum may be performed according to any method known in the art, as for instance disclosed in Maxian et al, 2021. In particular, a peptide is cytotoxic when the peptide at a given concentration leads to propidium iodide uptake in at least 20% of the cells after incubation in culture medium in the presence of 10% (v / v) human serum for 8 hours, as determined by fluorescence microscopy (compared to the positive control of incubation in 2.5% (w / v) Triton-X 100). More specifically, the test may be performed as follows: 105cells are washed with phosphate- buffered saline and re-suspended in culture medium with 10% (v / v) human serum and the peptide at a concentration of 20 µM (or without the peptide as a negative control, or 2.5% Triton-X- 100 as a positive control). The samples are incubated at 37°C for 8 h. Five μl of 50 µg / ml propidium iodide (PI) are then added to the samples and after 5 min at room temperature in the dark, fluorescence is measured with a fluorescence spectrometer using an excitation wavelength (λex) of 536 nm and an emission wavelength (λem) of 617 nm. PI-uptake is calculated from the percentage of PI-positive cells in medium alone (P0) and in the presence of peptide (PX) according to the following equation: 100 ∗ ( ^^ − ^^ ) % ^^ ^^_ ^^ ^^ ^^ ^^ ^^ ^^ =^^ 0( ^^100− ^^0) whereby Triton-X-100 (2.5%) is used to determine 100% PI- positive cells (P100). If PI-uptake for the peptide sample is at least 20%, the peptide is considered to be cytotoxic. In the context of the present invention, the test whether a peptide has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)) may be performed according to any method known in the art, as for instance disclosed in Avrahami & Shai, 2004. In particular, a 0.5% erythrocyte solution in phosphate-buffered saline is exposed to the respective peptide (e.g. at 1 µM or 10 µM or 20 µM or 50 µM) at 37°C for 1h; hemolysis is determined by measuring optical density of the cell supernatants at 415 nm. More specifically, the assay may be performed as follows: Whole venous blood of healthy volunteers is collected in citrate tubes. Erythrocytes are isolated by centrifuging the blood for 10 min at 2,000 x g and subsequently washing twice in PBS. A 0.5% erythrocyte solution in PBS is exposed to the peptides, e.g. at 1 µM or 10 µM or 20 µM or 50 µM. After 1 h at 37°C under static conditions, the erythrocyte suspensions are centrifuged and the optical density of the supernatants is determined at 415 nm. The percentage of hemolysis may be calculated relative to a positive control (e.g. 1% Triton X-100). The present invention further relates to the following embodiments: Embodiment 1. A peptide comprising a variant of the amino-acid sequence IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1), - preferably wherein the peptide is cytotoxic to a glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro, and - preferably wherein the peptide has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl-IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)), and - wherein the amino acid sequence comprises 1-8 amino acid substitutions independently selected from: - substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group or by P, and - substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 12, by another amino acid selected from said group or by any one of L, I, V, F, A, W and V or by P; preferably for use in prevention or treatment of a cancer. Embodiment 2. The peptide of embodiment 1, wherein the variant has the sequence IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7(SEQ ID NO: 7), wherein each of X1, X2, X3, X4, X5, X6, and X7is an amino acid independently selected from the group consisting of E, K, R, L, I, V, F, A, W, V and P, preferably from the group consisting of E, K, R, L, I, V, F, A, W and V, more preferably from the group consisting of E, K, R, L, W and V; optionally wherein one amino acid in the sequence IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7(SEQ ID NO: 7) selected from the group of L, V, F, A, I, W, Y or Q, with the exception of X1-X7, is replaced by another amino acid selected from said group or by P. Embodiment 3. The peptide of embodiment 2, wherein: X1 is E, K or R; X2is E, K, R, L, I, V, F, A, W, or V; X3is E, K or R; X4is E, K, R, L, I, V, F, A, W, or V; X5is E, K, R, L, I, V, F, A, W, or V; X6is E, K or R; and X7is E, K, R, L, I, V, F, A, W, or V. Embodiment 4. The peptide of embodiment 3, wherein: X1 is E, K or R; X2is K, L, I or V; X3is E, K or R; X4is K, L, I, V, F, A, W, or V; X5is R, L, I or V; X6is E, K or R; and X7is R, L, I or V. Embodiment 5. The peptide of embodiment 4, wherein: X1is E or K; X2 is K or L; X3is E or R; X4is K or W; X5is R or V; X6is E or K; and X7is R or L. Embodiment 6. The peptide of any one of the previous embodiments, wherein the variant has a sequence selected from the group consisting of IGKEFKRIVERKWRFLRELVRPLR (SEQ ID NO: 2), IGKKFKRIVRRKKRFLRKLVRPLR (SEQ ID NO: 3), IGKEFKRIVERKWRFLRKLVRPLR (SEQ ID NO: 4), IGKEFLRIVERKWRFLRKLVRPLL (SEQ ID NO: 5) and IGKEFLRIVERKWRFLVKLVRPLL (SEQ ID NO: 6). Embodiment 7. A peptide comprising the amino-acid sequence IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1) for use in prevention or treatment of a cancer. Embodiment 8. The peptide of any one of embodiments 1 to 7, wherein the entire amino acid sequence of the peptide consists of said amino-acid sequence or said variant of the amino acid sequence. Embodiment 9. A peptide which is a fragment of the peptide of any one of embodiments 1 to 7, wherein the fragment comprises at least the amino-acid sequence KRIVERKKRFLR (SEQ ID NO: 93), preferably KRIVERKKRFLREL (SEQ ID NO: 58), optionally having 1-6 amino acid substitutions independently selected from: - substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group or by P, and - substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 7, by another amino acid selected from said group or by any one of L, I, V, F, A, W and V or by P; preferably wherein the fragment is cytotoxic to a glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro and wherein the fragment has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)); preferably for use in prevention or treatment of a cancer. Embodiment 10. The peptide of embodiment 9, wherein the fragment has the sequence X2RIVX3RKX4RFLX5(SEQ ID NO: 51), preferably X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 14), wherein each of X2, X3, X4, X5and X6 is an amino acid independently selected from the group consisting of E, K, R, L, I, V, F, A, W, V and P, preferably from the group consisting of E, K, R, L, I, V, F, A, W and V, more preferably from the group consisting of E, K, R, L, W and V; optionally wherein one amino acid in the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 14) selected from the group of L, V, F, A, I, W, Y or Q, with the exception of X2-X6, is replaced by another amino acid selected from said group or by P. Embodiment 11. The peptide of embodiment 10, wherein the fragment has the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 14), wherein: X2is E, K, R, L, I, V, F, A, W, or V; X3 is E, K or R; X4is E, K, R, L, I, V, F, A, W, or V; X5is E, K, R, L, I, V, F, A, W, or V; and X6is E, K or R. Embodiment 12. The peptide of embodiment 11, wherein the fragment has the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 14), wherein: X2 is K, L, I or V; X3is E, K or R; X4is K, L, I, V, F, A, W, or V; X5is R, L, I or V; and X6is E, K or R. Embodiment 13. The peptide of embodiment 12, wherein the fragment has the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 14), wherein: X2is K or L; X3is E or R; X4is K or W; X5is R or V; and X6is E or K. Embodiment 14. The peptide of any one of embodiments 9 to 13, wherein the fragment has a sequence selected from the group consisting of KRIVERKWRFLREL (SEQ ID NO: 53), KRIVRRKKRFLRKL (SEQ ID NO: 54), KRIVERKWRFLRKL (SEQ ID NO: 55), LRIVERKWRFLRKL (SEQ ID NO: 56) and LRIVERKWRFLVKL (SEQ ID NO: 57). Embodiment 15. The peptide which is a fragment according to any one of embodiments 9 to 14, wherein the length of the peptide is 12-23 amino acids, preferably 13-22 amino acids or even 14-21 amino acids, more preferably 14-20 amino acids or even 14-19 amino acids, even more preferably 14-18 amino acids or even 14- 17 amino acids, yet even more preferably 14-16 amino acids or even 14-15 amino acids, especially 14 amino acids. Embodiment 16. The peptide of any one of the previous embodiments, wherein the peptide is less cytotoxic to a fibroblast cell line than to the glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro. Embodiment 17. The peptide of any one of the previous embodiments, wherein the peptide is N-terminally modified, preferably with an acetyl, hexanoyl, decanoyl, myristoyl, PEGyl, propionyl or dye moiety, and / or C-terminally modified, preferably with an amide, PEGyl, amino-hexanoyl or dye moiety. Embodiment 18. The peptide of any one of the previous embodiments, wherein the peptide comprises an N-terminal acetyl moiety and / or a C-terminal amide moiety. Embodiment 19. The peptide of any one of the previous embodiments, wherein the length of the peptide is 14-50 amino acids, preferably 24-40 amino acids, in particular 24-30 amino acids. Embodiment 20. The peptide of any one of the previous embodiments, for use in prevention or treatment of a cancer, wherein the cancer selected from the group consisting of brain cancers such as glioblastomas, breast cancers, colon cancers, esophageal cancers, prostate cancers, bladder cancer, kidney cancers, endometrial cancers, thyroid cancers, gastric cancers, liver cancers, lung cancers, pancreatic cancers, uterine cancers, tracheal cancers, testicular cancers, cervical cancers, head and neck cancers, skin cancers, bone cancers, pancreatic cancers, sarcomas, and ovarian cancers, in particular glioblastomas and sarcomas. Embodiment 21. The peptide of any one of the previous embodiments, for use in the prevention or treatment of a cancer, wherein the peptide is administered in combination with cancer immunotherapy, radiation therapy or chemotherapy. Embodiment 22. The peptide of any one of the previous embodiments, for use in the prevention or treatment of a cancer, wherein the peptide is administered as a neoadjuvant therapy. Embodiment 23. The peptide for any one of the previous embodiments, for use in the prevention or treatment of a cancer, wherein the peptide is administered intravenously. Embodiment 24. A method, comprising obtaining a pharmaceutical composition comprising the peptide of any one of embodiments 1 to 23; and administering the pharmaceutical composition to an individual, wherein the individual has a cancer or is at risk of developing the cancer. The present invention is further illustrated by the following figures and examples, without being restricted thereto. Fig. 1 – Peptide OP-145I12K is not toxic to human cells, but kills cancer cells. The peptide was cytotoxic towards glioblastoma cells, but not fibroblasts as observed in uptake of membrane- impermeable dye propidium iodine upon exposure of the cells to the peptide in presence of human serum for about 8h. Fig. 2 - Peptide OP-145I12Kis cytotoxic towards glioblastoma cells already at low concentrations. The peptide was cytotoxic towards glioblastoma already after an hour exposure of the cells to the peptide as it was observed in uptake of membrane- impermeable dye propidium iodide (PI) in presence of human serum. Results were means of at least two independent experiments performed in duplicates. Fig. 3 – Sequence alignments. Alignment of parent peptide OP-145 and inventive peptide OP-145I12K(SEQ ID NO: 1) as well as the inventive sequence variants SEQ ID NOs: 2-6 which also share the I12K mutation. Fig. 4 – Cytotoxicity against tumor cells. Activities of the inventive peptides were compared to activities of known peptides LL-37 and OP-145 (derivative of LL-37). Activities tested are anticancer and hemolytic activities (for 1h treatment with peptides) according to de Breij et al., 2018, and Malanovic et al., 2015, for 1-48 hour treatment of cancer cells. Hemolytic activity is expressed as MHC5% showing the minimal hemolytic concentration tolerated by FDA (= 5% hemolysis) while anticancer activity is expressed as effective concentration killing 50 % cancer cells (EC50%) Peptides are considered as non hemolytic. n.t. not tested. Anticancer activity is tested using cell viability assay in 2 D ( PI permeability assay). Fig. 5 – Cytotoxicity against tumor spheroids. Activities of inventive peptides were compared to activities of known peptide LL-37. Activities tested are anticancer and hemolytic activities (for 1h treatment with peptides) according to de Breij et al., 2018, and Malanovic et al., 2015, for 1-48 hour treatment of cancer cells. Hemolytic activity is expressed as MHC5% showing the minimal hemolytic concentration allowed by FDA (= 5% hemolysis) while anticancer activity is expressed as effective concentration killing 50 % cancer cells (EC50%) Peptides are considered as non hemolytic-*not hemolytic as higher concentrations were not tested. Anticancer activity was tested in 3D spheroids using celltiter glow assay (=ATP metabolic activity assay). Fig. 6 – Anti-tumor activity of peptide with SEQ ID NO: 3 and LL-37. (A) Morphological changes upon peptide exposure in breast and lung cancer spheroids after 48h incubation. Pictures were taken on Nikon Eclipse Ti2 light microscope in 100X magnification. Scale bars indicate 100 µm. (B) Effect of Nera-3 and LL-37 on cell viability of 3D lung cancer spheroids. 2500 cells per 100µl (per well) were used for spheroid formation. Cell viability was assessed by CellTiterGlo 3.0 (Promega, Germany). Lysis solution of CellToxGreen (Promega) was used as positive control. 0.01% HAc was used as vehicle control. (C) Effect of LL-37 on breast cancer spheroids assessed analogously to B. 5000 cells per 100 µl were used for spheroid formation. Example 1 – Anticancer properties of peptide OP-145I12K and sequence variants Materials & Methods Peptides: The peptides prepared by solid phase strategies on an automated multiple peptide synthesizer (SyroII, MultiSyntech, Witten, Germany) as described previously (Hiemstra et al, 1997). The purity of the peptides was >95%, as determined by UPLC-MS (Acquity, Waters, Milford, Ma). Peptide integrity was confirmed using Maldi-Tof mass spectrometry (Microflex, Bruker, Bremen, Germany), showing the expected molecular masses. The lyophilized peptides were stored at -20°C until use, then dissolved in H2O with 0.01% acetic acid to a stock of 10 mg / ml, and aliquots were stored at -20°C. Cytotoxicity against human dermal fibroblasts: Human dermal fibroblasts (PromoCell GmbH, Heidelberg, Germany) were cultivated in fibroblast growth media-2 (PromoCell GmbH). All cells were kept in a 5% CO2atmosphere at 37°C. Cells were cultured to ~90% confluence and then detached by accutase (PAA, Pasching, Austria). Enzymic activity was stopped with PBS containing 10% fetal bovine serum. Cells were washed with PBS and re-suspended in the culture medium. Approximately 1x105cells were incubated with 0-80 µM peptide for 1-8 h at 37°C. Five μl of 50 µg / ml propidium iodide (PI, Invitrogen, Camarillo, CA) were added to the samples and after 5 min at room temperature in the dark fluorescence was measured with a fluorescence spectrometer (SPEX Fluoro Max-3 spectrofluorimeter, Horiba Scientific, Irvine, CA) using an excitation wavelength (λex) of 536 nm and an emission wavelength (λem) of 617 nm. Cytotoxicity was calculated from the percentage of PI-positive cells in medium alone (P0) and in the presence of peptide (PX) according to equation 1: 100 ∗ ( ^^ ^ ^^ − ^^ ^^ ^^ ^^ ^^ ^^ =^− ^^ ) % ^^ 0( ^^100− ^^0) (1) whereby Triton-X-100 (2.5%) was used to determine 100% PI- positive cells (P100). Data may be expressed as IC50values, i.e. the lowest peptide concentration that lyses ≥50% of the cells. Cytotoxicity against cancer cells: Glioblastoma cells LN229 were purchased from ATCC (American Type Culture Collection, Manassas, VA, USA) and cultured in Dulbecco’s Modified Eagle Medium (DMEM) with GlutaMAXTM (Gibco®, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% human serum to known protocols (see e.g. Maxian et al, 2021). At 90% confluence cells were passaged with accutase (Gibco®, Thermo Fisher Scientific, Waltham, MA, USA). All cells were kept in 5% CO2at 37 °C and periodically checked for mycoplasma. Cells were collected, resuspended in respective media and diluted to a concentration of 106cells / mL. Cytotoxicity of the peptides against the glioblastoma cells was assessed as described in the paragraph above. Cytotoxicity tests with malignant glioma cell line U87, pancreatic cancer cell line PANC-1 and MUG Lucifer sarcoma cell lines (see Karner et al, 2023) were performed in a similar manner. Hemolysis assay: Whole venous blood of healthy volunteers was collected in citrate tubes. Erythrocytes were isolated by centrifuging the blood for 10 min at 2,000 x g and subsequently washed twice in PBS. A 0.5% erythrocyte solution in PBS was exposed to the peptides at the respective concentrations. After 1 h at 37°C under static conditions, the erythrocyte suspensions were centrifuged and the optical density of the supernatants was determined at 415 nm. The percentage of hemolysis was calculated relative to the positive control (1% Triton X-100). Results In order to test if OP-145I12K(IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1)) was well tolerated by human cell lines, hemolysis and cytotoxicity assay in fibroblasts were performed. In comparison to parent peptide OP-145, OP-145I12Kwas not hemolytic to human erythrocytes. The peptide did not lyse the human erythrocytes even at higher concentrations. This beneficial behavior was also observed for the variant peptide with SEQ ID NO: 3 and is expected for further I12K variants described herein (see also the alignment in Fig. 3 which underscores their similarity). Furthermore, for OP-145112K,no cytotoxicity towards human fibroblast, but increased cytotoxicity towards a glioblastoma tumor cell line was observed (Fig. 1). Toxicity towards glioblastoma cell line LN229 was already observed at 10 µM peptide and increased with time and concentration (Fig. 2), indicating already compromised membrane at very low peptide concentration allowing PI to enter the cell. This increase was more significant when peptide was incubated with glioblastoma for 8h. The EC50 values for 8 h were estimatedaround 15±3 µM showing that OP-145I12Ksignificantly permeabilized50 % of glioblastoma cells at ~15µM. Higher concentration of peptide resulted in shorter incubation time for the same effect. Importantly, OP-145I12Kshowed toxicity towards tumor cells in presence of human serum. Cytotoxicity was also observed against malignant glioma cell line U87, pancreatic cancer cell line PANC1 and MUG Lucifer sarcoma cells (incubation times: 0.1-7h). Cytotoxic behavior against the tumor cell lines was also observed for the variant peptide with SEQ ID NOs: 2 and 3 and is expected for further I12K variants described herein (see also the alignment in Fig. 3 which underscores their similarity). Example 2 – Further anticancer properties of peptide OP-145I12K and sequence variants Further studies were conducted with the peptides, with two- dimensional cultures (see Fig. 4) and spheroids (see Figs. 5-7). As shown in Fig. 6A, when the peptides were added to lung and breast cancer spheroids (A549 and MCF-7 cells, respectively), both cancer spheroids became darker with increasing peptide concentration, indicating cancer cell death that is correlating well with the decrease in cell viability observed for both peptides. At lower concentration, the spheroids were tightly packed and the morphology resembled untreated cancer spheroids, but the cells began to lose their connection to each other and the morphology began to change, becoming more irregular and uniform on the surface. In the case of lung spheroids, the size of the spheroids decreased and a halo of cellular debris was visible, which was more prominent in the case of LL-37. For both peptides, cancer spheroids treated with high peptide concentrations resulted in loosened and dissociated spheroid cells. This is in contrast to the positive control – the lysis buffer, which resulted in complete dissolution of the spheroids and cells, indicating complete lysis of the cells. Pancreatic carcinomas and melanomas do not form very tightly packed spheroids, but when exposed to peptides, the spheroids became more loosened and dissociated into smaller aggregates. This disintegration was more pronounced when clear cell carcinoma was treated with peptides. Cancer spheroids were no longer dense and became darker, indicating a death process. In summary, these results show that anticancer activity of the peptides of the invention is excellent. Non-patent references Avrahami & Shai. "A new group of antifungal and antibacterial lipopeptides derived from non-membrane active peptides conjugated to palmitic acid." Journal of Biological Chemistry 279.13 (2004): 12277-12285. de Breij, A., et al. "Prevention of Staphylococcus aureus biomaterial-associated infections using a polymer-lipid coating containing the antimicrobial peptide OP-145." Journal of Controlled Release 222 (2016): 1-8. Chen, Keqiang, et al. "The potentials of short fragments of human anti-microbial peptide LL-37 as a novel therapeutic modality for diseases." Frontiers in Bioscience-Landmark 26.11 (2021): 1362-1372. Felicio, Mario R., et al. "Peptides with dual antimicrobial and anticancer activities." Frontiers in chemistry 5 (2017): 5. Gaspar, Diana, A. Salomé Veiga, and Miguel ARB Castanho. "From antimicrobial to anticancer peptides. A review." Frontiers in microbiology 4 (2013): 294. Haisma, Elisabeth M., et al. "LL-37-derived peptides eradicate multidrug-resistant Staphylococcus aureus from thermally wounded human skin equivalents." Antimicrobial agents and chemotherapy 58.8 (2014): 4411-4419. Hiemstra HS, et al. The identification of CD4+ T cell epitopes with dedicated synthetic peptide libraries. Proc Natl Acad Sci U S A 1997 Sep 16;94(19):10313-8. Ishii, Nobuaki, et al. "Frequent Co‐Alterations of TP53, p16 / CDKN2A, p14ARF, PTEN Tumor Suppressor Genes in Human Glioma Cell Lines." Brain pathology 9.3 (1999): 469-479. Karner, Christina, et al. "Targeting epigenetic features in clear cell sarcomas based on patient-derived cell lines." Journal of Translational Medicine 21.1 (2023): 54. Kuroda, Kengo, et al. "The human cathelicidin antimicrobial peptide LL-37 and mimics are potential anticancer drugs." Frontiers in oncology 5 (2015): 144. Mader, Jamie S., and David W. Hoskin. "Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment." Expert opinion on investigational drugs 15.8 (2006): 933-946. Malanovic, Nermina, et al. "Phospholipid-driven differences determine the action of the synthetic antimicrobial peptide OP- 145 on Gram-positive bacterial and mammalian membrane model systems." Biochimica et Biophysica Acta (BBA)-Biomembranes 1848.10 (2015): 2437-2447. Maxian T, et al. Effect of L- to D-Amino Acid Substitution on Stability and Activity of Antitumor Peptide RDP215 against Human Melanoma and Glioblastoma. Int J Mol Sci. 2021 Aug 6;22(16):8469. Ön, Ayse. “Membrane permeabilization of Gram-negative bacteria by antimicrobial peptides derived from the human cathelicidin LL-37.” (2017), Graz University of Technology, master thesis. Piktel, Ewelina, et al. "The role of cathelicidin LL-37 in cancer development." Archivum immunologiae et therapiae experimentalis 64 (2016): 33-46. Piller, Paulina. “Mode of action of LL-37 derived antimicrobial peptides in Enterococcus hirae.” (2019), Graz University of Technology, master thesis. Weber, Günther, et al. "Human antimicrobial protein hCAP18 / LL-37 promotes a metastatic phenotype in breast cancer." Breast cancer research 11 (2009): 1-13.

Claims

Claims 1. A peptide comprising a variant of the amino-acid sequence IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1), - wherein the peptide is cytotoxic to a glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro, and - wherein the peptide has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)), and - wherein the amino acid sequence comprises 1-8 amino acid substitutions independently selected from: - substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group or by P, and - substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 12, by another amino acid selected from said group or by any one of L, I, V, F, A, W and V or by P; preferably for use in prevention or treatment of a cancer.

2. The peptide of claim 1, wherein the variant has the sequence IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7(SEQ ID NO: 7), wherein each of X1, X2, X3, X4, X5, X6, and X7 is an amino acid independently selected from the group consisting of E, K, R, L, I, V, F, A, W, V and P, preferably from the group consisting of E, K, R, L, I, V, F, A, W and V, more preferably from the group consisting of E, K, R, L, W and V; optionally wherein one amino acid in the sequence IGKX1FX2RIVX3RKX4RFLX5X6LVRPLX7(SEQ ID NO: 7) selected from the group of L, V, F, A, I, W, Y or Q, with the exception of X1-X7, is replaced by another amino acid selected from said group or by P.

3. The peptide of claim 2, wherein: X1 is E or K;X2is K or L; X3is E or R; X4is K or W; X5is R or V; X6is E or K; and X7 is R or L.

4. The peptide of claim 3, wherein the variant has a sequence selected from the group consisting of IGKEFKRIVERKWRFLRELVRPLR (SEQ ID NO: 2), IGKKFKRIVRRKKRFLRKLVRPLR (SEQ ID NO: 3), IGKEFKRIVERKWRFLRKLVRPLR (SEQ ID NO: 4), IGKEFLRIVERKWRFLRKLVRPLL (SEQ ID NO: 5) and IGKEFLRIVERKWRFLVKLVRPLL (SEQ ID NO: 6).

5. A peptide comprising the amino-acid sequence IGKEFKRIVERKKRFLRELVRPLR (SEQ ID NO: 1) for use in prevention or treatment of a cancer.

6. A peptide which is a fragment of the peptide of any one of claims 1 to 5, wherein the fragment comprises at least the amino-acid sequence KRIVERKKRFLREL (SEQ ID NO: 58) optionally having 1-6 amino acid substitutions independently selected from: - substitution of an amino acid selected from the group of L, V, F, A, I, W, Y or Q by another amino acid selected from said group or by P, and - substitution of an amino acid selected from the group of E, K and R, with the exception of K at position 7, by another amino acid selected from said group or by any one of L, I, V, F, A, W and V or by P; wherein the fragment is cytotoxic to a glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro and wherein the fragment has a hemolytic activity which is lower than the hemolytic activity of peptide OP-145 (acetyl- IGKEFKRIVERIKRFLRELVRPLR-amide (SEQ ID NO: 50)); preferably for use in prevention or treatment of a cancer.

7. The peptide of claim 6, wherein the fragment has the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 14), wherein each of X2, X3, X4, X5and X6is an amino acid independently selected from the group consisting of E, K, R, L, I, V, F, A, W, V and P, preferably from the group consisting of E, K, R, L, I, V, F, A, W and V, more preferably from the group consisting of E, K, R, L, W and V; optionally wherein one amino acid in the sequence X2RIVX3RKX4RFLX5X6L (SEQ ID NO: 14) selected from the group of L, V, F, A, I, W, Y or Q, with the exception of X2-X6, is replaced by another amino acid selected from said group or by P.

8. The peptide of claim 7, wherein the fragment has a sequence selected from the group consisting of KRIVERKWRFLREL (SEQ ID NO: 53), KRIVRRKKRFLRKL (SEQ ID NO: 54), KRIVERKWRFLRKL (SEQ ID NO: 55), LRIVERKWRFLRKL (SEQ ID NO: 56) and LRIVERKWRFLVKL (SEQ ID NO: 57).

9. The peptide of any one of claims 1 to 8, wherein the peptide is less cytotoxic to a fibroblast cell line than to the glioblastoma cell line at a concentration of 20 µM in presence of human serum in vitro.

10. The peptide of any one of claims 1 to 9, for use in prevention or treatment of a cancer, wherein the cancer selected from the group consisting of brain cancers such as glioblastomas, breast cancers, colon cancers, esophageal cancers, prostate cancers, bladder cancer, kidney cancers, endometrial cancers, thyroid cancers, gastric cancers, liver cancers, lung cancers, pancreatic cancers, uterine cancers, tracheal cancers, testicular cancers, cervical cancers, head and neck cancers, skin cancers, bone cancers, pancreatic cancers, sarcomas, and ovarian cancers, in particular glioblastomas and sarcomas.

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