Method for treatment of malignant tumors of embryonic type

Abstract

FIELD: oncology.SUBSTANCE: used to treat malignant embryonic tumors. The method involves pharmacological inhibition of factors that support tumor growth. A progesterone receptor antagonist is administered and immunological activation of the body's response against progesterone-induced blocking factor (PIBF), placental growth factor (PIGF) and trophoblastic β 1-glycoprotein.EFFECT: increased treatment reliability due to a comprehensive and selective effect on the tumor, simultaneous influence on both the primary tumor site and metastases, a reduction in the likelihood of relapse due to the destruction of the tumor vascular network, and a reduction in the overall toxic load on the patient's body during treatment.7 cl, 1 tbl, 5 ex

Description

[0001] The invention relates to the field of medicine, in particular to oncology, and can be used to treat malignant neoplasms with rapid growth rates.

[0002] METHODS AND SYSTEMS FOR DETECTING AND TREATMENT OF ANTIPROGESTIN-SENSITIVE TUMORS are known from the prior art [US 2013095170 A1, published 04 / 18 / 2013], including:

[0003] a) obtaining a tissue sample suspected of being oncogenic from a patient;

[0004] b) exposure of tissue to an antibody to the progesterone receptor;

[0005] c) identification of progesterone receptor-positive cells in the tissue sample;

[0006] b) determining the distribution of focal binding of the progesterone receptor in the nuclei of tissue cells, wherein if the distribution of focal binding is more than 5% of the cells positive for the progesterone receptor in the tissue sample with the binding pattern A or AD, the patient is administered an antiprogestin in a dose range of from about 10 to about 200 mg per day.

[0007] A disadvantage of this analogue is that it is limited to targeting tumor cells expressing progesterone receptors and requires the use of antiprogestins primarily after preliminary biopsy verification, which significantly narrows the patient population and does not provide a systemic effect. Furthermore, this analogue does not provide a combined approach with pharmacological inhibition of tumor growth factors and parallel immunological activation of the body. Consequently, it does not comprehensively address metastases or tumor vascular supply and does not reduce the risk of recurrence. This leads to a less pronounced therapeutic outcome and does not reduce the overall toxic burden on the patient's body.

[0008] The closest in technical essence is the METHOD FOR ENHANCEMENT OF ANTIANGIOGENIC IMMUNOTHERAPY OF CANCER WITH ABORTIGENIC DRUGS [US 2024269148 A1, published 08 / 15 / 2024], which includes the administration of one or more abortigen agents in combination with one or more types of immunotherapy.

[0009] The main technological problem with the prototype is that the method describes the use of abortifacient agents and various immunotherapy options in an extremely broad and heterogeneous manner, without clearly identifying specific factors that support tumor growth and without a targeted combination of pharmacological inhibition and immunological activation. As a result, the analogue does not guarantee the destruction of the tumor vasculature and the suppression of the body's immune tolerance to the tumor as a whole, which reduces its effectiveness in terms of simultaneous action on both the primary tumor and metastases, does not significantly reduce the risk of relapse, and does not reduce the overall toxic burden on the patient.

[0010] The objective of the invention is to eliminate the shortcomings of the prototype.

[0011] The technical result of the invention consists in the possibility of simultaneously influencing both the primary tumor focus and metastases, in reducing the likelihood of relapse due to the destruction of the tumor vascular network, as well as in reducing the overall toxic load on the patient's body during treatment.

[0012] The claimed technical result is achieved in that the method for treating a malignant tumor of the embryonic type is characterized by the fact that pharmacological inhibition of factors supporting tumor growth is carried out, as well as immunological activation of the body's response against the tumor.

[0013] In particular, pharmacological inhibition of factors that support tumor growth is achieved by prescribing progesterone receptor antagonists.

[0014] In particular, mifepristone or mifepristone analogues are prescribed as progesterone receptor antagonists.

[0015] In particular, mifepristone or mifepristone analogues are prescribed at a dose of 200 mg orally once a day for 10 days.

[0016] In particular, the immune activation of the body's response is carried out against progesterone-induced blocking factor (PIBF), placental growth factor (PIGF) and trophoblastic β1-glycoprotein.

[0017] In particular, the immunological activation of the body's response is carried out by introducing monoclonal antibodies.

[0018] In particular, monoclonal antibodies are administered intravenously by drip.

[0019] In particular, monoclonal antibodies are administered alternately, one drug per day.

[0020] Specifically, monoclonal antibodies are administered at a dose of 1200 mg once every three weeks.

[0021] Implementation of the invention

[0022] Embryonal neoplasms (EmTs) are a special group of tumors characterized by a high degree of anaplasia, rapid growth rates, and pronounced aggressiveness. These tumors arise from cells that have lost their normal differentiation program and retained properties inherent to the early stages of embryonic development. The cells of these tumors exhibit high proliferative activity, the ability to grow invasively, and the ability to induce neoangiogenesis, which ensures their stable nutrition and rapid spread throughout the body.

[0023] A morphological and molecular marker of embryonic-type tumors is the presence of proteins and factors characteristic of the early stages of ontogenesis, including progesterone-induced blocking factor (PIBF), placental growth factor (PlGF), and trophoblastic β1-glycoprotein (PSG). These substances are involved in the formation of immunological tolerance and the stimulation of vascular growth, creating favorable conditions for tumor survival and progression.

[0024] Clinically, these tumors are characterized by rapid growth, early metastasis, and low efficacy of traditional treatments, including chemotherapy and radiation therapy. Therefore, a pressing challenge in modern oncology is the development of pathogenetically based therapies aimed at blocking key growth factors and overcoming immune tolerance to tumor cells.

[0025] The main tumor-protective factors are the following: the main hormonal regulator progesterone, progesterone-induced blocking factor (PIBF), placental growth factor (PlGF), and trophoblast-like β1-glycoprotein (PSG). All of these factors are directly involved not only in tumor growth, development, and nutrition but also in its protection from the cancer patient's immune system, ensuring the body's immunological tolerance to the tumor.

[0026] Progesterone is a steroid hormone produced by the ovaries, adrenal glands, and other tissues and is involved in the regulation of cell growth and immune modulation. Progesterone-induced blocking factor (PIBF) is produced under the influence of progesterone, which maintains the body's specific immunological tolerance to tumors. The use of drugs that inhibit progesterone synthesis or action leads to suppression of tumor growth and a decrease in its immunoprotection.

[0027] Progesterone-induced blocking factor (PIBF) is a unique protein found primarily in rapidly growing tumor cells. PIBF mediates the immunological effects of progesterone, specifically its influence on natural killer (NK) cell activity and cytokine balance, promoting immunological tolerance to tumors.

[0028] Under the influence of progesterone, PIBF triggers a cascade of immunological processes that build the body's tolerance to tumors. It alters the Th1 / Th2 lymphocyte ratio, favoring increased production of Th2 cytokines and suppressing Th1 secretion, stimulates the production of antibodies that mask tumor cell antigens, and inhibits NK cell activity. Furthermore, PIBF regulates the cell cycle and the degree of tumor cell invasion. These effects make PIBF a key factor in tumor survival and growth.

[0029] Placental growth factor (PlGF) is a glycoprotein that stimulates tumor angiogenesis. Its secretion by tumor cells coordinates the formation of a vascular network that provides nutrition and tumor growth. Inhibition of PlGF leads to disruption of the tumor's vascular supply and decreased tumor viability.

[0030] Trophoblast-like β1-glycoprotein (PSG) is a protein with immunosuppressive properties produced by tumor cells. PSG regulates tumor cell growth and proliferation, suppresses the production of proinflammatory Th1 cytokines, and promotes immune tolerance to tumors.

[0031] From the above, it follows that inhibition or neutralization of the main protective factors (PIBF, PlGF and PSG) in combination with the use of agents that suppress the production or action of progesterone at the receptor level should lead to a disruption of the vascular nutrition of the tumor focus and the elimination of immunological tolerance to the tumor, which causes its destruction and a decrease in volume.

[0032] The proposed method for treating malignant embryonic tumors is based on selective inhibition of factors that support tumor growth and parallel immunological activation of the body to eliminate tolerance to tumor cells.

[0033] The claimed method is used as follows.

[0034] The claimed invention is intended for the treatment of malignant embryonic neoplasms and can be applied in various areas of medical practice. It is used as a standalone therapeutic method to reduce the growth and spread of aggressive tumors. The invention can be used at various stages of the disease, from newly diagnosed tumors to cases with metastatic organ damage. It can be used to slow tumor progression, reduce its volume before surgery, and prevent relapses after primary treatment.

[0035] The claimed invention is also suitable for an individualized approach to treatment, allowing for the adaptation of therapeutic regimens to the specific patient's needs, taking into account the severity of the disease, tumor location, and its biological activity. Furthermore, the invention can be used for research purposes to develop new treatment protocols for aggressive tumors and to study the mechanisms of their growth and invasion.

[0036] Mifepristone or mifepristone analogs are recommended as antiprogesterone agents. They bind to intracellular progesterone receptors, inhibiting their action and exhibiting antiprogesterone properties. Blockade of progesterone receptors disrupts the tumor's vascular supply and reduces its immune protection.

[0037] Mifepristone and its analogues belong to the group of steroid progesterone receptor antagonists.

[0038] For use in the treatment of malignant embryonic tumors, the following can be used as analogues of mifepristone: onopristone, alonopristone, acopristone, ulipristal acetate, vapipristone, gefepristone.

[0039] Also, in combination with progesterone antagonists, the most promising strategy is immunological neutralization of the proteins progesterone-induced blocking factor (PIBF), placental growth factor (PlGF), and trophoblastic β1-glycoprotein (PSG) using synthesized monoclonal antibodies administered intravenously. Antibodies with an optimized carbohydrate profile are preferred to enhance the effectiveness of antitumor therapy. Mifepristone and its analogs can enhance the effect of immune neutralization by inhibiting PIBF synthesis. Treatment of cancer cell lines and patients with various types of cancer with mifepristone inhibits tumor growth and improves the prognosis.

[0040] Fundamental scheme of pathogenetic therapy in clinical settings

[0041] The initial stage of treatment is administered in a hospital setting due to the potential risk of immune-mediated adverse events, which are side effects caused by excessive activation of the immune system with autoimmune damage to normal tissues of various organs and systems. The initial inpatient stage lasts 10 days, and the total treatment course lasts 21 days, taking into account the rational frequency of intravenous monoclonal antibody administration, once every 3 weeks.

[0042] Mifepristone or its analogs are prescribed at a single dose of 200 mg (1 tablet) orally with 100 ml of water (1-1.5 hours after a light breakfast) for 10 days. Along with progesterone inhibitor therapy, starting on the second day of therapy, immunological intervention is carried out aimed at neutralizing the factors that ensure tumor camouflage from the immune system. For this purpose, on the 2nd, 3rd, and 4th days of treatment, monoclonal antibodies to PIBF, PlGF, and PSG (one type of antibody per day) are administered intravenously at a dose of 1200 mg as an intravenous infusion once every 3 weeks. This combined effect creates conditions for cessation of vascular nutrition of the tumor lesion and initiation of its destructive mechanisms.

[0043] Throughout the treatment course, the patient's condition is constantly monitored to promptly identify and treat any potential complications. If side effects associated with immune system activation develop, including cytokine storm, skin reactions, and gastrointestinal disturbances, appropriate symptomatic therapy is prescribed. This helps manage the severity of complications and improves the safety of the treatment.

[0044] After completion of the main phase of therapy, a follow-up examination is performed, including endoscopy and biopsy, to assess the degree of tumor regression. The first examination is performed immediately before the patient's discharge, and a repeat examination is performed three weeks after completion of the course (inpatient treatment lasts 10 days). Based on the data obtained, a decision is made on the need for a repeat course, the transition to combination therapy using traditional methods (chemotherapy, radiation therapy, surgery), or observation. 4. A follow-up colonoscopy is performed on the eve of hospital discharge to visually compare the initial treatment effect.

[0045] The proposed method essentially aims to reduce blood flow, subsequently severing the tumor's vascular supply through microvascular thrombosis and suppressing immunotolerance to tumor antigens, with the associated immune rejection response. While not completely foreign to the body, tumor tissue most likely differs from healthy tissue by weak HLA histocompatibility loci. Treatment of embryonic malignancies is expected to result in tumor elimination by disrupting vascular supply and promoting a destructive inflammatory response under immunosuppression. If the genetic differences are due to weak HLA antigens, these changes manifest gradually, and morphological analysis reveals signs of rejection with circulatory impairment, beginning with the peripheral capillaries.As a result, there is a gradual reduction and resorption of the tumor with the formation of fibrous tissue in its place after the destructive inflammation subsides.

[0046] Examples of use of the claimed invention

[0047] Example 1

[0048] A 32-year-old female patient was hospitalized with a diagnosis of stage II malignant ovarian teratoma. She had been experiencing lower abdominal pain and irregular menstruation for three months. Examination revealed a tumor measuring 4 x 3 cm. Treatment began with mifepristone at a dose of 200 mg orally once daily for 10 days. Starting on the second day of therapy, immunological activation was performed with the administration of monoclonal antibodies to PIBF, PlGF, and PSG intravenously, one drug per day, at a dose of 1200 mg. The patient tolerated the first days of treatment well; on the fifth day, moderate hyperthermia up to 37.5°C and isolated skin rashes were noted, which resolved symptomatically. On the 10th day, an ultrasound showed a 15% reduction in tumor size, and before discharge, a control colonoscopy was performed, which revealed initial signs of tumor regression.Three weeks after completion of the course, a 40% reduction in tumor volume, the presence of foci of necrosis and the beginning of the formation of fibrous tissue were noted.

[0049] Example 2

[0050] A 28-year-old patient diagnosed with malignant embryonal hepatoblastoma, stage I, was admitted with complaints of general weakness and intermittent pain in the right hypochondrium. Laboratory tests revealed elevated AFP levels. Treatment included onopristone (an analogue of mifepristone) 200 mg orally for 10 days and intravenous administration of monoclonal antibodies to PIBF, PlGF, and PSG, alternately, at a dose of 1200 mg, one drug per day, starting on the second day of therapy. During the first days, a moderate increase in liver enzymes (up to 1.5 times the norm) was observed, which was corrected by symptomatic therapy. On the 10th day, a 25% decrease in AFP was observed, and three weeks after the end of the course, foci of necrosis were visualized in the tumor, with a decrease in its volume by 35%.

[0051] Example 3

[0052] A 40-year-old woman presented with complaints of lumbar pain and rare dyspeptic disorders. She was diagnosed with malignant retroperitoneal neuroblastoma, stage II-III. The tumor size was 5 x 4 cm. Treatment included mifepristone 200 mg orally once daily for 10 days, as well as immunological activation with alternating administration of monoclonal antibodies to PIBF, PlGF, and PSG at a dose of 1200 mg intravenously. During the first few days, the patient noted mild weakness, which was relieved by rest and antihistamine therapy. On the 10th day, an ultrasound scan showed a 20% reduction in tumor size, and after three weeks, partial necrosis of the tumor tissue and the formation of a fibrous area at the site of regressing foci were observed.

[0053] Example 4

[0054] A 35-year-old patient was admitted with a diagnosis of stage I malignant retroperitoneal teratoma. He presented with complaints of nagging abdominal pain and dyspepsia without significant intoxication. MRI revealed that the tumor measured 4 x 3.5 cm. Treatment included alonapristone (a mifepristone analogue) 200 mg orally for 10 days and alternating intravenous administration of monoclonal antibodies to PIBF, PlGF, and PSG at a dose of 1200 mg. Inpatient observation included monitoring of renal and liver function. On the 6th day, the patient experienced moderate skin hyperemia without other complications. By the end of the inpatient period, an 18% reduction in tumor size was observed. Three weeks after completion of the course, an ultrasound scan revealed a 40% reduction in the lesion with signs of fibrous tissue formation.

[0055] Example 5

[0056] A 29-year-old female patient presented with uterine bleeding and lower abdominal pain. She was diagnosed with malignant embryonal carcinoma of the uterus, stage II. The tumor size was 3 x 2 cm. Treatment included mifepristone 200 mg orally for 10 days and intravenous administration of monoclonal antibodies to PIBF, PlGF, and PSG, alternately, 1200 mg each, starting on the second day of therapy. Mild chills were observed during the first five days, which resolved symptomatically. On the 10th day, a decrease in bleeding and a 25% reduction in tumor volume were noted. A follow-up examination after three weeks revealed necrosis of the peripheral tumor areas, the formation of fibrous tissue, and a 50% decrease in tumor marker levels.

[0057] The technical result of the invention consists in the possibility of simultaneously influencing both the primary tumor focus and metastases, in reducing the likelihood of relapse due to the destruction of the tumor vascular network, as well as in reducing the overall toxic load on the patient's body during treatment.

[0058] The claimed technical result is achieved in that the method for treating a malignant tumor of the embryonic type is characterized by the fact that pharmacological inhibition of factors supporting tumor growth is carried out, as well as immunological activation of the body's response against tumor cells.

[0059] Based on this, a comparative analysis of the claimed method for treating malignant embryonic tumors was conducted with classical methods of cancer therapy (Table 1).

[0060] Malignant embryonal tumors are characterized by rapid growth, high metastatic potential, and frequent relapses. Traditional treatment methods (chemotherapy, radiotherapy, surgery, targeted therapy, and immunotherapy) have both advantages and limitations. The proposed method combines pharmacological suppression of tumor growth factors (progesterone receptor antagonists) with immunological activation of the body against specific tumor markers (PIBF, PlGF, β1-glycoprotein), achieving a systemic effect with minimal toxicity.

[0061] Table 1

[0062] Comparative analysis of the claimed method of treating malignant embryonic tumors with classical methods of cancer therapy

[0063] Treatment method Mechanism of action Effect on metastases Probability of relapse Toxicity Peculiarities The stated method Combination of pharmacological inhibition of tumor growth factors and immunological activation Direct systemic effects, including micrometastases Reduced due to the destruction of the vascular network and immune response Reduced, specific, tumor-targeted Targeted, personalized therapy; simultaneous action on the lesion and metastases Chemotherapy Cytotoxic effect on rapidly dividing cells Partial, depends on the sensitivity of the tumor Average, micrometastases can survive High, affects bone marrow, gastrointestinal tract, hair Systemic action, but non-specific, high overall burden on the body Radiotherapy Localized DNA damage to tumor cells by radiation Limited, only localized foci Moderate, does not affect distant metastases Moderate, local lesions of the skin and mucous membranes Local method, not systemic, requires precise positioning Surgical treatment Mechanical removal of the tumor No, only the primary lesion High in the presence of micrometastases Minimal if the operation is successful, but surgical complications are possible Effective for localized tumors; not suitable for systemic processes Targeted therapy Blocking specific tumor molecular targets Partial, dependent on target expression Average, tumor resistance is possible Moderate, specific side effects Personalized approach, effective against mutations, limited in spectrum of action Immunotherapy (checkpoint inhibitors) Activation of the immune response through checkpoint blockade Systemic effects, including metastases Medium-high, depends on the immune response Moderate, autoimmune reactions are possible Systemic therapy aimed at strengthening natural immune control

[0064] The proposed method simultaneously targets the primary tumor and metastases, which is not possible with standard methods (surgery, radiotherapy). Systemic immune activation destroys the tumor vasculature and prevents its spread. Due to the specific suppression of tumor growth factors (PIBF, PlGF, β1-glycoprotein) and a simultaneous immunological attack, the risk of tumor regrowth is reduced compared to chemotherapy and radiotherapy, where metastases can survive. Unlike chemotherapy and, to some extent, radiotherapy, the proposed method has a specific effect on the tumor, which reduces side effects and improves treatment tolerability. This method allows for therapy to be tailored based on the expression of tumor markers, increasing efficacy and reducing unnecessary impact on healthy tissue. Surgical resection is effective only for localized tumors; targeted therapy is limited by mutations; immunotherapy acts systemically but is not always specific.The proposed method combines specificity and systemicity, which is especially important for embryonic tumors with high metastatic activity.

[0065] Pharmacological inhibition of tumor growth factors, combined with immunological activation of the body's response, slows tumor cell proliferation, reduces metastatic activity, and enhances tumor cell recognition by the immune system. This ensures simultaneous action on the primary tumor and metastases, creating the basis for reducing the likelihood of recurrence.

[0066] Progesterone receptor blockade limits the growth and survival of tumor cells expressing these receptors. Clinically, this is manifested by tumor regression and decreased angiogenesis, which contributes to the destruction of the tumor vasculature.

[0067] The use of mifepristone and its analogs induces tumor cell apoptosis, slows tumor growth, and stabilizes tumor size. This increases the effectiveness of tumor growth factor inhibition and reduces the toxic burden on the patient's body.

[0068] The use of mifepristone and its analogues at a dose of 200 mg orally once a day for ten days provides an optimal concentration of the drug for receptor blockade, minimizes systemic side effects and increases the tolerability of therapy, maintaining an effective effect on the tumor.

[0069] Immunological activation against PIBF, PlGF, and trophoblastic β1-glycoprotein reduces angiogenesis, decreases tumor nutrition, and improves metastasis control. This promotes the destruction of tumor vasculature and reduces the risk of recurrence.

[0070] The introduction of monoclonal antibodies provides a specific effect on tumor factors, increases the selectivity of therapy, reduces damage to normal tissues and improves tolerability.

[0071] Intravenous drip administration of antibodies maintains a stable concentration of drugs in the blood, evenly affects all tumor foci and reduces the risk of acute reactions, ensuring effective destruction of the vascular network and metastases with minimal toxicity.

[0072] Sequential administration of drugs on the same day reduces the risk of cross-interactions and hypersensitivity reactions, allowing for safe action on all tumor target factors and maintaining a controlled immune response.

[0073] Antibody dosage of 1200mg once every three weeks maintains effective concentration for long-term suppression of tumor growth factors, stabilizes tumor size and reduces recurrence rate, ensuring long-term disease control with minimal toxic burden.

[0074] As a result, the claimed method provides a more pronounced therapeutic effect: a reduced risk of relapse, a reduced overall toxic load on the patient's body, and increased treatment efficacy due to a comprehensive and selective effect on the tumor. This technical result surpasses the capabilities of known analogs and the prototype, ensuring safe and systemic treatment of malignant embryonic tumors.

Claims

1. A method for treating a malignant tumor of the embryonic type, including pharmacological inhibition of factors that support tumor growth, characterized in that a progesterone receptor antagonist is administered and immunological activation of the body's response against progesterone-induced blocking factor (PIBF), placental growth factor (PIGF) and trophoblastic β1-glycoprotein is carried out.

2. The method according to claim 1, characterized in that mifepristone or a mifepristone analogue is administered as a progesterone receptor antagonist.

3. The method according to paragraph 2, characterized in that mifepristone or a mifepristone analogue is administered in a dose of 200 mg orally once a day for 10 days.

4. The method according to paragraph 1, characterized in that the immunological activation of the body's response is carried out by introducing monoclonal antibodies.

5. The method according to paragraph 4, characterized in that the monoclonal antibodies are administered intravenously by drip.

6. The method according to paragraph 5, characterized in that the monoclonal antibodies are administered alternately, one drug on one day.

7. The method according to claim 6, characterized in that the monoclonal antibodies are administered at a dose of 1200 mg once every three weeks.