TECHNICAL FIELD

The present invention relates to concomitant usage of vitamin C and PARP inhibitors in treatment of cancer patients or in elimination of symptoms of cancer patients where ETS fusion is detected.

PRIOR ART

Many developments are realized in treatment of cancer diseases. Surgery, radiotherapy and chemotherapy treatments can be applied depending on the phase of the disease. Important successes are obtained thanks to hormonal treatment method particularly in prostate and breast cancers.

In recent period, one of the important developments in cancer treatments is the ability to develop treatment methods which are unique for the person by means of the data obtained with genomic mapping. Moreover, thanks to the defined special mutations, the patients can be grouped; and treatments which are specific for the patient can be realized in this manner.

ETS transcription factor family genes;

E26 transformation specific family genes cover 29 genes in humans; and they play role in the development of various cancer diseases in humans and animals. The treatments in cancers developed as a result of fusion mutations which belong to the family are defined as ETS gene fusions.

ETS gene fusion is a type of mutation which can be observed in all cancer types particularly prostate, Ewing sarcoma and leukemia. In the study of Brenner et al, it has been shown that ETS gene fusion products enter into interaction with PARP1 and DNA-PK (known as DNA- protein kinase). This interaction (PARP1 and DNA-PK) is needed for tumor growth and formation which occurs by means of ETS fusion products. When methods which deactivate PARP1 (like PARP inhibitors) are applied, this interaction has not been observed in the negative tumors while the cancer cells with positive ETS fusion are affected. It has been mentioned that this pathway can be targeted in all cancers where ETS-PARP1 axis is positive.

As known, while ETS fusion products are substantially difficult to be targeted, targeting of proteins like PARP having regulating functions is accepted as a method applicable in cancer treatment. As DNA repair defect exists in BRCA1 and BRCA2 mutations, the usage of PARP inhibitors has provided important treatment successes. In ETS positive tumors, as shown by Brenner and Stewart studies, the usage of PARP inhibitors (olaparib, talazoparib, niraparib and the like) has shown dose-dependent effect. However, in ETS positive tumors, the usage of chemotherapy agent (temozolamide and the like) together with PARP inhibitor has become more effective.

For cancers having ETS fusion, in animal phase studies and cell culture studies, it has been observed that the usage of PARP inhibitor decelerates tumor growth but does not provide reduction of the size of the tumor. However, when an agent (like chemotherapy agents) which will form DNA damage is added, the tumor has been completely lost or substantially reduced in size.

In human studies, usage of chemotherapy combinations together with PARP inhibitors, which prevent DNA repair, leads to serious side effects. Because the unfavorable effects of chemotherapy on bone marrow are augmented with PARP inhibitors. It has been mentioned that when Olaparib is used together with paclitaxel in metastatic breast cancer, serious amount of bone marrow toxicity occurs. (Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A et al. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Research 2013:15:R88).

In chemotherapy combinations, the dose integrity and density of PARP inhibitors are needed to be reduced, in other words, the dose of the PARP inhibitors is needed to be reduced or is needed to be applied intermittently. However, dose-dependent effect of PARP inhibitors in ETS fusions is known. In other words, a better effect is obtained at higher dose.

Ewing sarcoma is the cancer type which occurs in bones or in the soft tissue around the bones and which has the most typical ETS fusions. (For instance like EWS-ETS; EWSR1- ERG, EWSR1-FLI1). This cancer type essentially begins in pelvis, in leg or arm bones; however, it may also occur in any bone. Even though important developments have been obtained in tumors with detected ETS fusion primarily in Ewing sarcomas and prostate cancer, the method, which can realize selective DNA damage and which will be combined with PARP inhibitors after understanding of the mechanism, will be able to provide the most effective result. However, a treatment has not been developed which will provide usage of PARP inhibitors at effective dose and which will provide selective toxic effect to the tissue with cancer.

In the known state of the art, in bone and soft tissue tumors, it is used in a combined manner with PARP inhibitors and together with chemotherapy treatment methods when required. In the present treatment method, not only PARP inhibitors are effective, and the toxicity risk is very high in case of combination with chemotherapy. It is known that the healthy cells of the patient are damaged in said treatment methods. Moreover, it is known that chemotherapy treatment method leads to toxic effect for patients.

As a result, because of the abovementioned problems, an improvement is required in the related technical field.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to concomitant usage of vitamin C and PARP inhibitors in treatment of cancer patients or in elimination of symptoms for cancer patients where ETS fusion is detected primarily in Ewing sarcoma and prostate cancers, for eliminating the abovementioned disadvantages and for bringing new advantages to the related technical field.

The main object of the present invention is the concomitant usage of vitamin C and PARP inhibitors for providing treatment for cancer patients where all ETS fusion is detected.

Another object of the present invention is the concomitant usage of vitamin C and PARP inhibitors where chemotherapy application to the patient is eliminated and where efficient dose can be used continuously.

In order to realize the abovementioned objects and the objects which are to be deducted from the detailed description below, the present invention relates to concomitant usage of vitamin C and PARP inhibitors in treatment of cancer patients or in elimination of symptoms for cancer patients where ETS fusion is detected. Thanks to this, the tumors where ETS fusion is detected can be treated. In a possible embodiment of the present invention, said vitamin C is used at a value between 10 grams and 187 grams. Thanks to this, high dose C vitamin is used and treatment of tumors where ETS fusion is detected is provided.

In a possible embodiment of the present invention, vitamin C is used at a value between 0.6 g/kg and 2 g/kg.

In a possible embodiment of the present invention, vitamin C is preferably at a value between 0.6 g/kg and 1 .5 g/kg.

In a possible embodiment of the present invention, PARP inhibitor is at least one of PARP 1 , PARP 2 and PARP 3 inhibitors.

In a possible embodiment of the present invention, PARP inhibitor is preferably PARP 1 inhibitor.

In a possible embodiment of the present invention, said PARP inhibitor is at least one of olaparib, veliparib, nirapalib, rucaparib PARP inhibitors or one of PARP inhibitors being developed.

In a possible embodiment of the present invention, PARP 1 inhibitor is preferably olaparib, talazoparib, niraparib.

In a possible embodiment of the present invention, PARP inhibitor is between 200 mg and 400 mg.

In a possible embodiment of the present invention, PARP inhibitor is preferably 300 mg.

BRIEF DESCRIPTION OF THE FIGURES

In Figure 1 , the view of Positron Emission Tomography (it will be called as PET hereafter) of the patient having Ewing Sarcoma tumor after concomitant usage of vitamin C and PARP inhibitors is given.

In Figure 2, the view of lung Computer tomography (it will be called as CT hereafter) of the patient before concomitant usage of vitamin C and PARP inhibitors is given. In Figure 3, the view of lung Computer tomography (it will be called as CT hereafter) of the patient after concomitant usage of vitamin C and PARP inhibitors is given.

In Figure 4, the view for the 1 ^st patient a) PET/CT imaging before treatment, b) the image which shows reduction of the tumor taken after concomitant usage of vitamin C and PARP inhibitor, c) the image of recurrence of the disease in the period where only PARP inhibitor is used after the patient stops vitamin C treatment, d) the image obtained after beginning the treatment with concomitant usage of vitamin C and PARP inhibitor is given.

In Figure 5, the view for the 2 ^nd patient a) PET image before beginning treatment, b) tomography image before beginning treatment, c) tomography image which shows apparent reduction in the tumor size after 1 month after beginning the vitamin C and PARP inhibitor treatment is given.

DETAILED DESCRIPTION OF THE INVENTION

In this detailed description, the subject matter relates to usage of PARP inhibitors and vitamin C in treatment of cancers or in elimination of symptoms for cancers where ETS fusion is detected, and is explained with references to examples without forming any restrictive effect only in order to make the subject more understandable.

In tumors with ETS fusion, it is known that the tumor is decelerated by inhibiting PARP system which is responsible for DNA repair, in other words, by using PARP inhibitors and that a very good tumor response is obtained if an agent which will realize additional DNA damage like chemotherapy is added to the treatment.

It is known that when vitamin C is added to the body at a high dose, its effect is pro-oxidant. It is known that high dose of vitamin C leads to hydrogen peroxide formation. The formed hydrogen peroxide interacts with the free iron pool increased in cancer cells and leads to formation of free oxygen radicals and leads to selective DNA damage macro molecule damage in tumor cells.

In the known state of the art, ETS fusions interact with the PARP system and provide advancing of cancer. In our invention, PARP inhibitors are used for providing reduction of the efficiency of PARP enzymes. Our subject matter invention relates to concomitant usage of PARP inhibitors and vitamin C in treatment of tumors having ETS fusion or provides elimination of the symptoms resulting from these diseases.

In our invention, as PARP inhibitors, inhibitors are used which are effective on one or some of PARP enzymes or agents are used which may lead to PARP function loss. Said PARP inhibitors will be used at doses defined to be efficient.

In the preferred application of our invention, at least one of the Olaparib, veliparib, nirapalib, rucaparib inhibitors is used as PARP inhibitor. However, all agents which may lead to PARP function loss can be used in our invention.

In the principle embodiment of our invention, at least one of Olaparib, talazoparib and niraparib is used as the PARP 1 inhibitor.

In a preferred embodiment of our invention, said vitamin C is used at a high dose. Vitamin C is used such that it is at least 10 grams and at most 187 grams. In a preferred embodiment, vitamin C is used at a value between 1 gram/kg and 2 grams/kg. In the possible embodiment of our invention, vitamin C is at a value between 1 gram/kg and 1.5 grams/kg.

The subject matter usage of vitamin C together with PARP inhibitors targets tumor cells without damaging healthy cells in patients. Thanks to this, the toxic side effects resulting from chemotherapy treatment method are eliminated and the healthy cells preserve their functions without being affected.

In Figure 1 , it has been observed that said tumor has reduced in size in an apparent manner, after the subject matter concomitant usage of vitamin C and PARP inhibitors.

In Figure 2, CT image taken from the lung of a patient having Ewing sarcoma tumor is given. As seen in Figure 2, there is a tumor which has a size which can cover the left lung part of the patient.

Totally 24 applications have been made to the patient within 2 months. Each of said applications comprises usage such that the amount of vitamin C is between 50 mg and 100 mg and PARP inhibitor is at a value between 200 mg and 400 mg. As a result of the applications, image as in Figure 3 is obtained. Vitamin C application has been planned for 3 times per week. Example

1 ^st Example

In the invention, as an example, there is a woman of 19 years old having Ewing sarcoma tumor at the left distal femur part. After 7 years in year 2015, metastasis has been detected in the lung region and the metastasis has been removed from the lung by means of surgical operation. In year 2017, metastasis has been observed again in the patient lung part. The secondly occurring metastasis has been removed from the lung by means of surgical operation. Afterwards, oral cyclo-phospho-amide and other complementary treatments have been applied. In year 2019, chemotherapy treatment has been applied for providing treatment resulting from metastasis. CT and PET images of the patient have been taken after this treatment method.

The subject matter concomitant usage of vitamin C and PARP inhibitors is applied to the patient after metastasis diagnosis. 24 applications comprising high dose vitamin C and PARP inhibitors have been realized to the patient. Each application comprises concomitant usage such that the amount of vitamin C is between 50 mg and 100 mg and PARP inhibitor (olaparib) is between 200 mg and 400 mg.

In Figure 4, for the 1 ^st patient, the PET images taken at the following times are given: a) The beginning of the treatment b) After 2 months application of high dose vitamin C and PARP inhibitor c) After stopping high dose vitamin C treatment and only using PARP inhibitor d) After beginning high dose vitamin C treatment again. In the PET images taken, as can also be understood in figures a), b), c) and d), 2 months after high dose vitamin C and PARP inhibitor are applied to the patient as described in the invention, response which is close to complete treatment has been obtained. However, the removal of high dose vitamin C from the treatment which leads to selective DNA damage as a result of treatment incompliancy of the patient has led to apparent development in the tumor. Afterwards by means of application of high dose vitamin C again, tumor response has been obtained again. Addition of an agent which can lead to DNA damage leads to serious side effects and bone marrow toxicity by means of PARP inhibitors. Therefore, high dose vitamin C as the agent, where PARP inhibitors will be used together in ETS fusions, occurs as the most efficient treatment option. After the final application, PET and CT images of the patient have been obtained. According to the obtained images, it has been observed that the tumor which exists in the left lung of the patient has reduced in size in an apparent manner. 2 ^nd Example

The 2 ^nd patient is Ewing sarcoma patient having kidney disease. 2 separate chemotherapies have been applied before beginning vitamin C and PARP inhibitor and the patient has faced serious chemotherapy side effects. In PET films of the patient taken before the treatment, tumor mass which nearly completely fills the abdomen is seen in Figure 5(a, b). The treatment has begun where PARP inhibitor and high dose vitamin C (50-100 grams) are applied 3-4 times per week. It is seen in the tomography that the tumor has reduced apparently at the 1 ^st month of the treatment. In Figure 5, for the 2 ^nd patient, the following is given: a) PET image before beginning the treatment, b) tomography image before beginning the treatment, c) tomography image showing the apparent reduction in the tumor one month after beginning vitamin C and PARP inhibitor treatment.

The protection scope of the present invention is set forth in the annexed claims and cannot be restricted to the illustrative disclosures given above, under the detailed description. It is because a person skilled in the relevant art can obviously produce similar embodiments under the light of the foregoing disclosures, without departing from the main principles of the present invention.