BACKGROUND OF THE INVENTION

Field of the Invention

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said. ASCII copy, created on Mar. 15, 2017, is named P14169-DO-sequence-listing_ST2.txt and is 94,208 bytes in size.

The instant invention provides for a new method of treating bone metastasis diseases in subjects, wherein said method preferably depends on whether the subject shows certain specific proteins levels in one or more body fluids prior to or during treatment, wherein said treatment comprises the administration of at least one pan αv integrin inhibitor to a subject, a medicament for use in said new methods, and a method of predicting the outcome of a treatment with at least one pan αv integrin inhibitor based on said specific protein levels in one or more body fluids of the subject.

More specifically, the instant invention provides for a new method of treating of treating bone metastasis diseases, preferably bone metastasis disease is derived from prostate cancer, breast cancer and/or cancer in subjects with at least one pan αv integrin inhibitor, preferably including the pan αv integrin inhibitor abituzumab or Intetumumab, wherein said subjects show certain specific protein levels in one or more body fluids prior to or during treatment.

Discussion of the Background

Bone metastases, or metastatic bone disease, is a class of cancer metastases that results from primary tumor invasion to bone. Bone is one of the most common locations for metastasis. [Coleman R E (October 2006). “Clinical features of metastatic bone disease and risk of skeletal morbidity”. Clin. Cancer Res. 12 (20 Pt 2): 6243s-9s.] While any type of cancer is capable of forming metastatic tumors within bone, the microenvironment of the marrow tends to favor particular types of cancer, including prostate, breast, and lung cancers. [Guise T (October 2010). “Examining the metastatic niche: targeting the microenvironment”. Semin. Oncol. 37 (Suppl 2): S2-14.] Particularly in prostate cancer, bone metastases tend to be the only site of metastasis. [Jimenez-Andrade J M, Mantyh W G, Bloom A P, Ferng A S, Geffre C P, Mantyh P W (June 2010). “Bone cancer pain”. Annals of the New York Academy of Sciences 1198: 173-81.]

Lung cancer, also known as carcinoma of the lung or pulmonary carcinoma, is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung by process of metastasis into nearby tissue or other parts of the body, including the liver, brain and bone. Most cancers that start in the lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. The main primary types are small-cell lung carcinoma (SCLC), and non-small-cell lung carcinoma (NSCLC). Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). As a class, NSCLCs and metastases thereof are relatively insensitive to chemotherapy, compared to small cell carcinoma. A wide variety of chemotherapies are used in metastatic NSCLC, unfortunately with little effect to date. Small-cell carcinoma or small-cell lung cancer (SCLC) is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointesinal tract. SCLC usually metastasizes widely very early on in the natural history of the tumor. Also in this case, the metastasis affects predominantely the bone, liver and brain.

Breast cancer develops from breast tissue. It most commonly develops in cells from the lining of milk ducts and the lobules that supply the ducts with milk. Cancers developing from the ducts are known as ductal carcinomas, while those developing from lobules are known as lobular carcinomas. In addition, there are more than 18 other sub-types of breast cancer. The diagnosis of breast cancer is regularly confirmed by taking a biopsy of the concerning lump. Once the diagnosis is made, further tests are done to determine if the cancer has spread beyond the breast and which treatments it may respond to. If the cancer has spread beyond the breast, the breast cancer presents as metastatic disease. The symptoms caused by metastatic breast cancer will depend on the location of metastasis. Common sites of metastasis include bone, liver, lung and brain.

The metastatic process is a multistep event and represents the most dreadful aspect of cancer. At the moment of diagnosis, cancers are frequently far advanced in their natural history, and the presence of metastases is a common event. In fact, approximately 30% of patients have detectable metastases at the moment of clinical diagnosis and a further 30% of patients have occult metastases. Metastases can be disseminated and they can infest different organs at the same time, or localize to a specific organ. In the case of localized disease, surgery is the treatment of choice; however recurrence and prognosis depend on many criteria such as: resectability, patient's clinical situation, and number of metastases.

After resection, recurrence is common, suggesting that micrometastatic foci are present at the moment of diagnosis. Systemic chemotherapy is an ideal setting but only few patients are cured by it, and in the majority systemic chemotherapy fails. Many physiological barriers and pharmacokinetic parameters contribute to decrease its efficacy.

Liver, lungs and lymph nodes are filtration organs and therefore inclined to metastasization. The poor chemosensitivity of metastases, peculiarly those of colorectal origin has forced many researchers to use methods for increasing the time and the concentration of drugs. The need for decreasing or limiting the side effects for this important and delicate organ led to the development of the technique of liver isolation for perfusion of antineoplastic agents. (K. R. Aigner, Isolated liver perfusion. In: Morris D L, McArdle C S, Onik G M, eds. Hepatic Metastases. Oxford: Butterworth Heinemann, 1996. 101-107). Since 1981, modifications and technical improvements have been continuously introduced. Liver metastases may be of different origin and their chemosensitivity may vary according to the histological type and their response in presence of heat.

There still exists a growing need in the art in order to develop new therapeutic strategies for treating cancer, especially metastases, systemically.

The object of the present invention therefore was to develop such a new strategy. It should be applicable to systemic treatment, and it should lower the dose and/or increase the efficiency of the cancer therapeutical agents to be applied. A further object was to normalize tumor vasculature to increase delivery of systemic therapeutics of tumor, i.e. to reset the tumor vasculature to the functionality of the vasculature of non-tumor tissue.

Thus, it is a preferred objective of the instant invention to provide a more effective, better tolerated treatment for humans, especially human cancer patients suffering from bone metastases, preferably bone metastases independent from their origin, thus preferably leading to enhanced overall survival (OS), progression-free survival (PFS), quality of life (QOL) and/or increased median survival.

Prostate cancer is the most commonly occurring cancer aside skin cancer in the US, and is the second most common cause of male cancer deaths. Prostate cancer is classified in four stages: Stage I prostate cancer is found in the prostate only and cannot be felt during a digital rectal exam nor is it visible by imaging. In stage II prostate cancer, the tumor has grown inside the prostate but has not extended beyond it, whereas in stage III, the cancer has spread outside the prostate, but to a minimal extent only. Often, prostate cancer in stage III will have spread only to nearby tissues, such as the seminal vesicles. Finally, in stage IV, the cancer has spread outside the prostate to other tissues, such as the lymph nodes, bones, liver, and/or lungs or brain.

The spectrum of prostate cancers that are progressing despite castrate levels of testosterone includes tumors that have shown varying degrees and durations of response to primary hormone treatment, and clinical manifestations that range from a rising prostate-specific antigen (PSA) alone, a rising PSA with osseous and/or soft-tissue spread, or a predominantly visceral disease pattern.

Currently approved treatment of prostrate cancer includes surgical castration, chemical castration, or a combination of surgical and chemical castration. Removal of the testes, the primary testosterone producing organ, reduces the levels of circulating androgens, to less than 5% of normal levels. This reduction in androgen levels inhibits prostate tumor growth. Although the anti-tumor effects of surgical castration are direct, the anti-tumor effects can be temporary. Surgical castration often leads to clonal selection of androgen-independent prostate tumor cells. This results in re-growth of the prostate tumor in a form that proliferates without testosterone or DHT Stimulation. Chemical castration (also called medical castration) is often substituted for surgical castration, as an initial treatment. Despite its high prevalence, treatment options for men having prostate cancer remain relatively limited and typically depend on the stage of the cancer.

Treatment options include surgical treatments such as radical prostatectomy, in which the prostate is completely removed and radiation, applied through an external beam that directs the dose to the prostate from outside the body or via low-dose radioactive seeds that are implanted within the prostate to kill cancer cells locally. Anti-androgen hormone therapy also is used in the treatment of prostate cancer, either alone or in conjunction with surgery or radiation. Hormone therapy typically aims at blocking the pituitary from producing hormones that stimulate testosterone production by use of castration or administration of hormone analogs and requires that patients have injections of these hormone analogs for protracted periods. Finally, chemotherapeutic approaches have been used to treat advanced prostate cancer, usually as a last resort when other approaches have failed. Since a couple of years, the combination of docetaxel and prednisone was established as the new standard of care for patients who have progressed on androgen deprivation.

None of the treatments described above are curative and prostate cancer being androgen dependent at first, often will progress despite surgical and hormonal-based therapies, and become resistant over time, leading to a cancer type which is called “hormone refractory cancer” or “castration resistant cancer” (CRPC).

Clinical disease manifestations of CRPC are commonly related to bone metastases and may include pain, pathologic fractures, and spinal cord compression, with local recurrences that may be associated with pelvic discomfort, renal dysfunction due to ureteral compression, bladder outlet obstruction, and sexual dysfunction. Further, while bone cancer is the predominant result of CRPC, patients may develop soft-tissue metastases (lymph node(s)) and visceral metastasis in liver, lung, brain, and other organs. Patients with CRPC are minimally responsive to chemotherapy and the majority of patients die due to progressive prostate cancer within 20 months of initiating treatment. Bisphosphonates are commonly used in patients with castrate-resistant prostate cancer who have bone metastases.

It has been shown that prostate tumors remain dormant and clinically undetectable until they begin to secrete angiogenic factors and down-regulate the expression of angiogenic inhibitors. In general, it can be stated that angiogenesis is critical to the genesis of prostate tumors. Therefore, it was not completely surprising that anti-angiogenic agents may inhibit prostate cancer cell growth.

In prostate cancer, tumor cells express an abnormal integrin repertoire and are surrounded by a markedly aberrant extracellular matrix (ECM). These changes have profound consequences, given the ability of each integrin to regulate specific cell functions. Expression of β3 and β1 subunits activates specific signaling pathways and support distinct cancer cell functions. β3 is uniquely required in cancer cells for increasing cdc2 levels as well as cdc2 kinase activity. These effects are specific for β3 and are not observed for β6. Up-regulation of β3 and β6 integrin variants has been described. Zheng et al. (Cancer Research 1999; 59, 1655-1664) used human prostate cancer cells isolated from sixteen surgical specimens, to show that these cells express αvβ3, whereas normal prostate epithelial cells do not. Similarly, αvβ6 was found to be expressed in adenocarcinoma (Azare et al.; Molecular and Cellular Biology 2007; 27, 4444).

The use of integrin inhibitors is likely to affect both cancer cell survival and angiogenesis since integrins are expressed by tumor cells as well as by endothelial cells. Although it is hard to discriminate between an effect on tumor growth and an effect on angiogenesis, a maximal response of these inhibitors can be predicted when the targeted integrin is expressed by both tumor and endothelial cells.

Bone is the most frequent metastatic site for prostate cancer. Bisanz et al. (Molecular Therapy 2005; 12, 634-643) illustrate a positive role for alpha-v integrins on prostate tumor survival in the bone. Analysis of human prostate cancer bone xenografts shows that intratumoral administration of liposome encapsulated human alpha-v siRNAs significantly inhibits the growth of PC3 tumors in bone and increases apoptosis of prostate tumor cells. Further studies (McCabe et al., Oncogene 2007; 26, 6238-6243) demonstrate that αvβ3 integrin activation on tumor cells is essential for the recognition of key bone specific matrix proteins. These data suggest that the αvβ3 integrin modulates prostate cancer growth in distant metastasis. Since integrins mediate the interactions between tumor cells and bone microenvironment and facilitate growth in bone, a potential application of the use of integrin inhibitors is to prevent prostate cancer bone lesions.

These lesions are osteoblastic and/or osteolytic and are frequently detected in prostate cancer patients (over 80% of prostate cancer patients have established bone metastasis at autopsy).

A recent study has shown that the αvβ3 integrin promotes bone gain mediated by prostate cancer cells that metastasize to the bone and point to αvβ3 as a potential therapeutic target to block prostate cancer osteoblastic lesions. Immunohistochemical analysis has demonstrated the presence of αv integrin in a large proportion of human prostate cancer tissues samples.

These and other results suggest that anti-integrin agents may have both direct and indirect antitumor activity. But there are only few clinical trials reporting that peptide or non-peptide integrin inhibitors are effective agents in prostate cancer therapy.

Therefore, there is a need to provide a method of treatment of bone metastases, preferably bone metastases of breast cancer, lung cancer and/or prostate cancer. Moreover, there is a especially high need to provide a method for the treatment of prostate cancer bone metastases, especially castration-resistant prostate cancer bone metastases.

Therefore, there is a also a need to provide a method of treatment of bone metastases from metastatic androgen independent prostate cancer (mAIPCa) and/or bone metastases from metastatic androgen dependent prostate cancer (mADPCa).

SUMMARY OF THE INVENTION

According to an aspect of the invention there is provided a method for identifying bone metastasis in a subject, preferably a human subject, that is susceptible to treatment with at least one pan αv integrin inhibitor, preferably Abituzumab, comprising determining said certain proteins levels in one or more body fluids, whereby a high level of one or more proteins selected from a first group of said specific proteins and/or a low level of one or more proteins from a second group of said specific proteins indicates the tumor is susceptible to said treatment.

Body fluids are preferably the liquids originating from inside the bodies of living subjects, preferably living human subjects. They include fluids that are excreted or secreted from the body as well as body water that normally is not excreted or secreted.

The body fluids can preferably specified by type, such as intracellular fluids, extracellular fluids, intravascular fluids (e.g. whole blood, blood and blood plasma), interstitial fluids, lymphatic fluids (sometimes regarded as a subtype of interstitial fluids), and transcellular fluids.

Preferred body fluids are selected from the group consisting of whole blood (preferably also referred to as “blood”), blood serum (preferably also referred to as “serum”), blood plasma (preferably also referred to as “plasma”), exudate, lymph, mucus, peritoneal fluid, saliva, sputum, tears and urine. Especially preferred body fluids are selected from the group consisting of Preferred body fluids are selected from the group consisting of whole blood (preferably also referred to as “blood”), blood serum (preferably also referred to as “serum”), and blood plasma (preferably also referred to as “plasma”). Especially preferred is blood plasma (preferably also referred to as “plasma”). Alternatively preferred is blood serum (preferably also referred to as “serum”), and whole blood (preferably also referred to as “blood”).

The threshold for categorization of patients into “low level” or “high level” for each of said specific proteins is preferably determined by listing of all available levels for that respective specific protein in the respective body fluid, then determining the median from this listing of said specific protein level values in said body fluid, and taking this median value as the threshold.

This threshold is preferably also referred to herein as median threshold. Preferably, said threshold or median threshold is determined in the population of subjects suffering from the respective bone metastasis disease as described herein. More preferably, said threshold or median threshold for the respective specific protein is determined from the body fluid of a plurality of subjects being part of a diseased subject population suffering from the respective bone metastasis disease.

For example, for determining said median threshold for one or more said specific proteins, body fluid samples (here: blood samples) are taken from 150 human subjects suffering from metastatic castrate-resistant prostate cancer (mCRPC) in order to obtain about 500 μL offer a preferred body fluid (here: blood plasma). The levels of the contained specific proteins of interest, e.g. STX1A are determined using an aptamer based protein detection system, e.g. the SomaLogic Proteomic Affinity Assay Method described in detail in the Experimental Section, whereby results for each protein of interest are represented by relative fluorescence readouts reported by the detection system. In an optional next step, the obtained raw data set can be simplified by removing the data of proteins not of interest, e.g. proteins that are known to be derived or affected by inadequate sample handling during plasma protein, such as platelet activation or cell lysis which may occur during the plasma preparation process. The thus obtained data set is then preferably subjected to steps such as data normalization procedures in order to obtain robust signals of the proteins of interest and estimates of the median protein levels across the study population of patients. Preferably, this data analysis process includes a cut-of optimisation. This procedure thus provides a median threshold of one or more specific proteins of interest, e.g. the median threshold for the protein STX1A. Taking this obtained median threshold, both said 150 human subjects suffering from metastatic castrate-resistant prostate cancer (mCRPC), as well as future human subjects suffering from mCRPC, can then be readily characterised as having a high level or a low level, respectively, of one or more specific proteins of interest, e.g. STX1A, with the predicted specific impact on the clinical outcome of the treatment with at least one pan αv integrin inhibitor, optionally in combination with one or more chemotherapeutic agents.

Preferably, the body fluid sampling and/or the evaluation of the median value for the respective specific protein is performed prior to treatment of the respective bone metastasis disease with said at least one pan αv integrin inhibitor. Preferably, patients are classified as “high level” if their respective specific protein level in said body fluid is higher than the median threshold. Accordingly, patients are preferably classified as “low level” if their respective specific protein level in said body fluid is lower than or equal to said median threshold.

More preferably, the threshold for categorization of patients into “low level” or “high level” for each of said specific proteins is preferably determined by listing of all available levels for that respective specific protein in the blood plasma, then determining the median from this listing of said specific protein level values in said blood plasma, and taking this median value as the threshold. This threshold is preferably also referred to herein as median threshold. Preferably, the blood plasma sampling and/or the evaluation of the median value for the respective specific protein is performed prior to treatment of the respective bone metastasis disease with said at least one pan αv integrin inhibitor. Preferably, patients are classified as “high level” if their respective specific protein level in said blood plasma is higher than the median threshold. Accordingly, patients are preferably classified as “low level” if their respective specific protein level in said blood plasma is lower than or equal to said median threshold.

Preferably, the respective bone metastasis disease in this regard is metastatic prostate cancer, more preferably metastatic castration-resistant prostate cancer (mCRPC). Preferably, the at least one pan αv integrin inhibitor comprises Abituzumab or Intetumumab). More preferably, the at least one pan αv integrin inhibitor is Abituzumab or Intetumumab. Especially preferred, the at least one pan αv integrin inhibitor is Abituzumab.

More preferably, the threshold for categorization of patients into “low level” or “high level” for each of said specific proteins is preferably determined by listing of all available levels for that respective specific protein in the blood plasma, then determining the median from this listing of said specific protein level values in said blood plasma, and taking this median value as the threshold. This threshold is preferably also referred to herein as median threshold. Preferably, the blood plasma sampling and/or the evaluation of the median value for the respective specific protein is performed prior to treatment of the respective bone metastasis disease with said at least one pan αv integrin inhibitor. Preferably, patients are classified as “high level” if their respective specific protein level in said blood plasma is higher than the median threshold. Accordingly, patients are preferably classified as “low level” if their respective specific protein level in said blood plasma is lower than or equal to said median threshold. Preferably, the respective bone metastasis disease in this regard is metastatic prostate cancer, more preferably metastatic castration-resistant prostate cancer (mCRPC). Preferably, the at least one pan αv integrin inhibitor comprises Abituzumab or Intetumumab). More preferably, the at least one pan αv integrin inhibitor is Abituzumab or Intetumumab. Especially preferred, the at least one pan αv integrin inhibitor is Abituzumab.

Methods to determine said threshold level and especially said median threshold level are known in the art. Examples of suitable technologies include, but are not limited to the SomaLogic technology, preferably the SomaLogic Proteomic Affinity Assay technology, SomaLogic SOMAscan™/V3/Version 10.5.1.1, ELISA (Enzyme-Linked Immuno-Sorbent Assays) technologies and variants thereof, including the RIA (Radio Immuno Assay) technology as high sensitivity variant, the 2D SDS-Polyacryamid electrophorese (SDS-PAGE) Mass Spectrometry technology, and Proximity Ligation Assay (PLA) technologies.

More specifically, the threshold for classification of patients into the ‘high’ and ‘low’ groups on the basis of plasma levels of the mentioned proteins is preferably the median plasma level across the patient population. The threshold may show a slight, but irrelevant dependency from the actual technology employed.

Preferably, protein plasma levels of samples that are to be classified are measured using the SomaLogic technology, preferably the SomaLogic Proteomic Affinity Assay technology (Somalogic, Inc., 2945 Wilderness PI, Boulder, Colo. 80301, USA, software package and version number as described herein) as described herein. The median plasma levels that are accordingly identified can be used as threshold for classification into ‘low’ and ‘high’ categories, preferably after the new SomaLogic patient profile is processed with data normalization steps, such as it has been performed in the analysis described herein. For example, the patient's pre-treatment proteomic profiles on 888 plasma protein levels—as it is prepared by the SomaLogic system—can advantageously be combined with existing pre-treatment data set for all samples, variance stabilization as implemented in the vsn2 package which was applied. Finally, the normalized patient's pre-treatment level for the specific protein of interest (median thresholds for predicitivity for radiologic PFS—MAPK11: 9.46, STX1A: 9.06, MAP2K2: 11.9, TNFRSF17: 12.5, RGMB: 11.0, LEPR:11.2, IL1B:11.1, ICAM3:10.4, F5:15.7, ANG:12.5, PIGR:12.6, TEK:11.3; all median thresholds are given as protein level units on a log 2 scale as measured by Somalogic technology and after variance-stabilizing normalization of the data set) as received from the clinical study described herein (PERSEUS study). In case no prior data set is available, or the technology to measure the plasma protein levels is not the SomaLogic technology, the median population plasma level—as it comes from the new technology or the new patient population (that preferably comprises at least 120 patients for the respective indication) is preferably termined first, then classification can be readily done on the basis of the new population median.

Especially preferably, patients are classified as “high level” if their respective specific protein level in said blood plasma is at least 2% higher, more preferably at least 5% higher, even more preferably at least 10% higher and especially at least 25% higher than said median threshold for the respective specific protein.

Especially preferably, patients are classified as “low level” if their respective specific protein level in said blood plasma is at least 2% lower, more preferably at least 5% lower, even more preferably at least 10% lower and especially at least 25% lower than said median threshold for the respective specific protein.

Preferably, said specific proteins according to the invention comprise

a) one or more proteins, selected from the group consisting of

DCN (Somamer ID: SL004081; UniProt ID: P07585),

F5 (Somamer ID: SL000622; UniProt ID: P12259),

ICAM3 (Somamer ID: SL003178; UniProt ID: P32942),

PIGR (Somamer ID: SL005797; UniProt ID: P01833),

STK17B (Somamer ID: SL016566; UniProt ID: 094768),

STX1A (Somamer ID: SL004304; UniProt ID: Q16623), and

TEK (Somamer ID: SL003200; UniProt ID: Q02763),

and/or

b) one or more proteins, selected from the group consisting of

ANG (Somamer ID: SL000003; UniProt ID: P03950),

IL1B (Somamer ID: SL001795; UniProt ID: P01584),

LEPR (Somamer ID: SL003184; UniProt ID: P48357),

MAP2K2 (Somamer ID: SL010501; UniProt ID: P36507),

MAPK11 (Somamer ID: SL007453; UniProt ID: Q15759),

RGMB (Somamer ID: SL010468; UniProt ID: Q6NW40), and

TNFRSF17 (Somamer ID: SL004672; UniProt ID: Q02223)

and/or preferably also proteins having at least 80%, more preferably at least 90%, even more preferably at least 95% and especially at least 99% sequence homology to said specific proteins.

More preferably, said specific proteins according to the invention comprise

a) one or more proteins, selected from the group consisting of

F5 (Somamer ID: SL000622; UniProt ID: P12259),

ICAM3 (Somamer ID: SL003178; UniProt ID: P32942),

PIGR (Somamer ID: SL005797; UniProt ID: P01833),

STX1A (Somamer ID: SL004304; UniProt ID: Q16623), and

TEK (Somamer ID: SL003200; UniProt ID: Q02763),

and/or

b) one or more proteins, selected from the group consisting of

ANG (Somamer ID: SL000003; UniProt ID: P03950),

IL1B (Somamer ID: SL001795; UniProt ID: P01584),

LEPR (Somamer ID: SL003184; UniProt ID: P48357),

MAP2K2 (Somamer ID: SL010501; UniProt ID: P36507),

MAPK11 (Somamer ID: SL007453; UniProt ID: Q15759),

RGMB (Somamer ID: SL010468; UniProt ID: Q6NW40), and

TNFRSF17 (Somamer ID: SL004672; UniProt ID: Q02223)

and/or preferably also proteins having at least 80%, more preferably at least 90%, even more preferably at least 95% and especially at least 99% sequence homology to said specific proteins.

More preferably, a high level as defined herein for one or more specific proteins in the respective body fluid, preferably in the blood plasma, of the patient is advantageous with respect to the clinical outcome, if said high level of said one or more specific proteins in said body fluid comprises one or more of the proteins selected from the group consisting of

DCN (Somamer ID: SL004081; UniProt ID: P07585),

F5 (Somamer ID: SL000622; UniProt ID: P12259),

ICAM3 (Somamer ID: SL003178; UniProt ID: P32942),

PIGR (Somamer ID: SL005797; UniProt ID: P01833),

STK17B (Somamer ID: SL016566; UniProt ID: 094768),

STX1A (Somamer ID: SL004304; UniProt ID: Q16623), and

TEK (Somamer ID: SL003200; UniProt ID: Q02763),

even more preferably one or more of the proteins selected from the group consisting of

F5 (Somamer ID: SL000622; UniProt ID: P12259),

ICAM3 (Somamer ID: SL003178; UniProt ID: P32942),

PIGR (Somamer ID: SL005797; UniProt ID: P01833),

STX1A (Somamer ID: SL004304; UniProt ID: Q16623), and

TEK (Somamer ID: SL003200; UniProt ID: Q02763),

and/or preferably also proteins having at least 80%, more preferably at least 90%, even more preferably at least 95% and especially at least 99% sequence homology to said specific proteins.

More preferably, a low level as defined herein for one or more specific proteins in the respective body fluid, preferably in the blood plasma, of the patient is advantageous with respect to the clinical outcome of the treatment of the respective bone metastasis disease with the at least one pan αv integrin inhibitor, if said low level of said one or more specific proteins in said body fluid comprises one or more of the proteins selected from the group consisting of

ANG (Somamer ID: SL000003; UniProt ID: P03950),

IL1B (Somamer ID: SL001795; UniProt ID: P01584),

LEPR (Somamer ID: SL003184; UniProt ID: P48357),

MAP2K2 (Somamer ID: SL010501; UniProt ID: P36507),

MAPK11 (Somamer ID: SL007453; UniProt ID: Q15759),

RGMB (Somamer ID: SL010468; UniProt ID: Q6NW40), and

TNFRSF17 (Somamer ID: SL004672; UniProt ID: 002223)

and/or preferably also proteins having at least 80%, more preferably at least 90%, even more preferably at least 95% and especially at least 99% sequence homology to said specific proteins.

