CN109481687A - The combination of CDK4/6 inhibitor joint HER2 inhibitor for curing gastric cancer - Google Patents
The combination of CDK4/6 inhibitor joint HER2 inhibitor for curing gastric cancer Download PDFInfo
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Abstract
The invention discloses the combinations of the CDK4/6 inhibitor joint HER2 inhibitor for curing gastric cancer.Claimed CDK4/6 inhibitor and HER2 inhibitor are preparing the application in composition；The composition is for treating the HER2 positive and drug resistant patients with gastric cancer.In past gastric cancer clinical research history, for patient after first-line treatment drug resistance, which kind of ineffective medicine/scheme, patient benefits little, therapeutic combination provided by the invention can achieve so good benefit effect, really belong to exception, which is that the present inventor is proposed based on preclinical study result for the first time, and carry out clinical research confirmation in patients, it is the landmark important breakthrough in one, gastric cancer field.
Description
Technical field
The present invention relates to the combinations of the CDK4/6 inhibitor joint HER2 inhibitor for curing gastric cancer.
Background technique
Asia is global gastric cancer most hotspot, and the annual neopathy of China, which is suffered from, accounts for the 47% of the whole world.Newest China's tumour
Registration statistical data shows that incidence gastric cancer rate and the death rate occupy national malignant tumor front three, seriously endangers compatriots' health.About
In staging evening (DISTANT METASTASES IN or local advanced), lose surgical radical treatment chance or postoperative when 80% Chinese gastric cancer patients are made a definite diagnosis
Recurrence and metastatic rate is very high, and drug therapy is later patient's essential therapeutic arsenals by stages.Between the past few decades, chemotherapy is always stomach
The foundation stone of cancer drug treatment, but benefit limited and toxicity for patient's bring and curing gastric cancer research is made to enter bottleneck period, evening greatly
5 years survival rates of phase patients with gastric cancer are hovered in 20-30%, and middle position Overall survival was difficult more than 12 months.
Currently, neoplasm targeted therapy is treatment hot spot, the successful application of anti-HER2 molecular targeted agents Herceptin is beaten
Chemotherapy of gastric cancer bottleneck has been broken, HER2 positive patient Overall survival is made to extend to about 16 months, this is landmark progress, so far
HER2 is also unique specific " star " therapy target in gastric cancer field.It has been clearly indicated that in the whole world and Chinese gastric cancer practice guidelines,
HER2 positive patient preferential recommendation Herceptin combined chemotherapy is as first-line treatment scheme.In gastric cancer, HER2 positive patient ratio
Example about 12-15%, and in HER2 positive patient, only about 50% patient can obviously obtain from Herceptin targeted therapy
Benefit, these patients obviously benefited with the extension of medication times it is most of all can after the treatment 8-9 months when occur it is resistance to
Medicine (secondary drug resistance), and there are also quite a few patients to drug initial drug-resistant.Drug resistance clinically is treated for first-line drug
Patients with gastric cancer afterwards, it may be said that helpless, subsequent two wires or three line therapeutic strategies are all based on greatly the experience choosing of clinician
It selects, even if some patientss can benefit from subsequent two wires or the treatment of three lines, benefits to be also little.Therefore, it is controlled after exploring drug resistance
Treating strategy becomes the most important thing.
It is well known that the main reason for drug resistance is drug therapy failure, the height heterogeneity of stomach cancer cell and swelling for complexity
Tumor microenvironment causes its resistance mechanism very complicated, and so far, gastric cancer field includes that the resistance mechanism of chemotherapeutics and targeted drug is equal
It is indefinite.
Summary of the invention
The object of the present invention is to provide the combinations of the CDK4/6 inhibitor joint HER2 inhibitor for curing gastric cancer.
Claimed CDK4/6 inhibitor and HER2 inhibitor are preparing the application in composition；The composition
For treating HER2 positive gastric carcinoma patient.
The present invention is also claimed CDK4/6 inhibitor and HER2 inhibitor and is preparing the application in composition；The combination
Object is for treating the HER2 positive and drug resistant patients with gastric cancer.
The present invention is also claimed CDK4/6 inhibitor and HER2 inhibitor and is preparing the application in composition；The combination
Object is for treating the HER2 positive and the drug resistant patients with gastric cancer of HER2 inhibitor.
The present invention is also claimed CDK4/6 inhibitor and HER2 inhibitor and is preparing the application in composition；The combination
Object is for treating patients with gastric cancer.
In any description above application, the active constituent of the composition is CDK4/6 inhibitor and HER2 inhibitor.
In any description above application, two kinds of ingredients can with leatherware body are as follows: CDK4/6 inhibitor 100mg × 21:HER2
Inhibitors 4 00mg × 28.
A kind of composition is also claimed in the present invention, and active constituent is CDK4/6 inhibitor and HER2 inhibitor；It is described
Composition is for treating HER2 positive gastric carcinoma patient.
A kind of composition is also claimed in the present invention, and active constituent is CDK4/6 inhibitor and HER2 inhibitor；It is described
Composition is for treating the HER2 positive and drug resistant patients with gastric cancer.
A kind of composition is also claimed in the present invention, and active constituent is CDK4/6 inhibitor and HER2 inhibitor；It is described
Composition is for treating the HER2 positive and the drug resistant patients with gastric cancer of HER2 inhibitor.
A kind of composition is also claimed in the present invention, and active constituent is CDK4/6 inhibitor and HER2 inhibitor；It is described
Composition is for treating as treatment patients with gastric cancer.
In any description above composition, two kinds of ingredients can with leatherware body are as follows: CDK4/6 inhibitor 100mg × 21:
HER2 inhibitors 4 00mg × 28.
Each medication cycle 28 days.The specific administrated method of each medication cycle are as follows: CDK4/6 inhibitor 100mg takes orally,
Once a day, continuous 3 weeks；HER2 inhibitors 4 00mg takes orally, once a day, continuous 4 weeks.
Any description above CDK4/6 inhibitor concretely SHR6390, can also be other.
Concretely pyrroles replaces Buddhist nun to any description above HER2 inhibitor, can also be other.
Any description above patients with gastric cancer concretely postoperative patient shifted of Radical Operation of Gastric Carcinoma, such as radical operation for carcinoma of stomach
The patient of liver metastasis afterwards.
The patient of any description above patients with gastric cancer as multiple transfer when concretely gastric cancer is made a definite diagnosis, such as multiple lymph node
Or peritonaeum shifts patient.
In past gastric cancer clinical research history, for patient after first-line treatment drug resistance, which kind of ineffective medicine/scheme is suffered from
Person's benefit is little, and therapeutic combination provided by the invention can achieve so good benefit effect, really belong to exception, which is
What the present inventor was proposed based on preclinical study result for the first time, and carry out clinical research confirmation in patients, it is gastric cancer
The landmark important breakthrough in one, field.
Detailed description of the invention
Fig. 1 is the identification of the secondary drug resistance gastric cancer PDX model of HER2 inhibitor.
Fig. 2 is the Pathomorphology consistency identification of PDX tissue before and after drug resistance.
Fig. 3 is the expression change that western blot method detects cell cycle several key molecules in the tissue of drug resistance front and back
Change.
Fig. 4 is in drug resistance PDX model with the tumor growth curve (A) and western after single medicine or drug combination
Blot method detects the expression variation (B) of cell cycle several key molecules before and after medication.
Fig. 5 is results of imaging comparison before and after one medication of patient.
Fig. 6 is neoplastic hematologic disorder marker (CEA, CA199, CA72.4) Comparative result before and after one medication of patient.
Fig. 7 is results of imaging comparison before and after two medication of patient.
Fig. 8 is neoplastic hematologic disorder marker (CEA, CA199, CA72.4) Comparative result before and after two medication of patient.
Specific embodiment
Embodiment below facilitates a better understanding of the present invention, but does not limit the present invention.Experiment in following embodiments
Method is unless otherwise specified conventional method.The experimental materials used in the following example is unless otherwise specified certainly
What routine biochemistry reagent shop was commercially available.Quantitative experiment in following embodiment is respectively provided with three repeated experiments, as a result makes even
Mean value.Mouse in embodiment is NOD/SCID (non-obese diabetes/severe combined immunodeficiency) mouse.In embodiment
CDK4/6 inhibitor is all made of SHR6390 (Hengrui Medicine), and the HER2 inhibitor in embodiment is all made of pyrroles for Buddhist nun (permanent auspicious doctor
Medicine).Patient is the volunteer of informed consent.
The it is proposed that embodiment 1, CDK4/6 inhibitor joint HER2 inhibitor for treating combine
It is reliable explore drug resistance after therapeutic strategy must can succeed by Study on Transformation, " preclinical study guidance is faced
Bed test is carried out " it is unique channel, it is based on this, the present inventor designs and carried out chain-type research.
Drug-resistant Mechanism Study is most important on condition that having optimal preclinical resistant models, based on conventional cell system
The resistant models of screening are no longer the optimal selections of drug resistance research due to very big with patient tumors feature difference.
The present inventor's early period, real-time endoscopic biopsy micro late gastric cancer tissue construction was extensive based on suffering from
Mouse subcutaneous transplanting tumor (patient-derived tumor xenograft, PDX) model of person's tumor tissues, establishes PDX
Tissue bank, it was confirmed that the high consistency of PDX tissue and patient tumors characteristic, the PDX model become the best mould of preclinical study
Type also provides optimal platform for building drug resistance PDX model.PDX group of the PDX tissue bank origin derived from the tumor tissues of multiple patients
Knit composition, the preparation method of each PDX tissue is equal are as follows: it is subcutaneous that specimens are seeded to mouse, long extremely to gross tumor volume
About 150-200mm3Size takes tumor tissues, is frozen.
Inventor has selected HER2 positive and the PDX mould sensitive to HER2 inhibitor from the PDX model library that it is established
Type is simulated patient's administration, is lasted about 8 months, construct HER2 inhibitor drug resistance PDX model using long-term intermittent revulsion.
The building process of the PDX model of HER2 inhibitor sensitivity and HER2 inhibitor drug resistance PDX model is following, and (pyrroles replaces
Buddhist nun is HER2 inhibitor): recovery PDX is organized from PDX tissue bank, and it is subcutaneous to be seeded to mouse, long to about 150- to gross tumor volume
200mm3Size (lasts about 1 month), start to give pyrroles for Buddhist nun and last about 3 months (stomach-filling, once a day, single
Dosage is 20mg/kg), Tumors display, which goes out, replaces Buddhist nun's drug resistance to the pyrroles of 20mg/kg；Separate tumor tissues, renewed vaccination to newly it is small
It is long to about 150-200mm to gross tumor volume in mouse3Size (lasts about 1 month), starts to give pyrroles for Buddhist nun and lasts about 3
Month (stomach-filling, once a day, single dose 40mg/kg), Tumors display goes out completely resistance to for Buddhist nun to the pyrroles of 40mg/kg
Medicine.C019, which is represented, inoculates the mouse after recovery PDX is organized 1 month, and S019, which is represented, gives pyrroles with 20mg/kg single dose
For the mouse after Buddhist nun 2 weeks, R019, which is represented, gives pyrroles with 40mg/kg single dose for the mouse after Buddhist nun 3 months.
The method of resistance test: inhibitor group gives pyrroles for Buddhist nun (stomach-filling, once a day, single dose 40mg/kg),
Control group gave isometric physiological saline, every 3 days measurement gross tumor volumes.The drug susceptibility result of C019 and R019 model is shown in
Fig. 1 average value of 5 mouse (every group be).C019 is highly sensitive for Buddhist nun to pyrroles, and pyrroles replaces tumour inhibiting rate > 100% of Buddhist nun.
R019 shows the height drug resistance that Buddhist nun is replaced to pyrroles.
The PDX tissue of C019, S019 and R019 carry out HE dyeing, as a result see Fig. 2.PDX tissue is lured after long-time drug
Rear Pathomorphology is led to be consistent.
PDX tissue (the PDX tissue of the PDX tissue of C019, the PDX tissue of S019 and R019) before and after drug resistance is turned
The sequencing of record group carries out signal path enrichment analysis to sequencing result and finds, relative to being organized before drug resistance, cell in tissue after drug resistance
The Abnormal regulation enrichment in period is most significant, is verified with western blot to tissue before and after drug resistance, discovery participates in cell week
Key molecule (cyclin D1, CDK4/6, pRb etc.) expression of period regulation significantly raises (Fig. 3) in organizing after drug resistance,
The downstream effect molecule Rb phosphorylation of especially CDK4/6 and cyclin D1 significantly increases.Therefore inventor speculates, cyclin
D1-CDK4/6 access may participate in gastric cancer HER2 targeted therapy drug resistance extremely, after combining CDK4/6 inhibitor or can becoming drug resistance
Therapeutic strategy, the hypothesis are verified in drug resistance PDX model.
PDX model (R019 mouse, every group of 5 mouse) grouping administration drug resistant to HER2 inhibitor:
First group (vehicle control group): physiological saline is given in stomach-filling once a day (oral), and single single volume is
100 μ l, continuous 3 weeks；
Second group (HER2 inhibitor group): stomach-filling once a day (oral) gives pyrroles for Buddhist nun, and single single volume is 100
μ l, single dose are " pyrroles replace Buddhist nun 40mg/kg ", continuous 3 weeks；
Third group (CDK4/6 inhibitor group): SHR6390 is given in stomach-filling once a day (oral), and single single volume is
100 μ l, single dose be " SHR6390 100mg/kg ", continuous 3 weeks；
4th group (CDK4/6 inhibitor combine HER2 inhibitor group): stomach-filling once a day (oral) give pyrroles for Buddhist nun with
SHR6390, single single volume are 100 μ l, and single dose is " pyrroles replaces Buddhist nun 40mg/kg " and " SHR6390100mg/kg ", are connected
It is 3 weeks continuous.
Every 3 days measurement gross tumor volumes, Fig. 4 A is as a result seen, CDK4/6 inhibitor, which combines HER2 inhibitor, has significant association
Same tumor-inhibiting action.
Go deep into Mechanism Study confirmation, after drug combination, participated in tissue the cell cycle key molecule (cyclin D1,
CDK4/6, pRb etc.) expression downward, especially pRb is significantly lowered, and cells arrest plays tumor-inhibiting action (Fig. 4 B) in the G1 phase.
The treatment curative effect of embodiment 2, CDK4/6 inhibitor joint HER2 inhibitor in patients with gastric cancer
One, the course of disease and treatment condition of patient one
Patient one: grandson * *, female
It is diagnosed within 2 months 2017 and turns out to be poorly differentiated adenocarcinoma cancer；Postoperative pathological pT4N1M0 (III phase) by stages, immunohistochemistry
Show that HER2 is positive (3+)；It is postoperative to carry out oxaliplatin fluorouracil based chemotherapy in March, 2017.
In August, 2017 check discovery hepatic metastases, considers disease progression, receive successively paclitaxel plus platinum (disease into
Exhibition), Irinotecan joint fluorouracil and Ah pa replace Buddhist nun (progression of disease), docetaxel combine fluorouracil (disease into
Exhibition), Paclitaxel liposome (progression of disease) multi-thread treatment, in July, 2018 check progression of disease, it is found that it is multi-thread the patient received
After treatment, disease still makes much progress.For this kind of patient, general prognosis is very poor.
In August, 2018 enters the clinical research of group inventor.2018.8.6 it controls to giving the 1st period drug during 2018.9.2
It treating, totally 28 days, specific medication are as follows: CDK4/6 inhibitor 100mg takes orally, once a day, continuous 3 weeks；HER2 inhibitors 4 00mg,
It is oral, once a day, continuous 4 weeks.2018.9.4 give human granulocyte stimulating factors 150 μ due to bone marrow suppression to 2018.9.8
G, qd rise white treatment.2018.9.10 to the 2nd period drug therapy is given during 2018.10.7, totally 28 days, specific medication was the same as the 1st
Period.2018.10.8 PET-CT check and routine CT check are carried out, effect PR (partial response) is commented.Fig. 5 A is treatment
Front and back PET-CT is as a result, Fig. 5 B is pretherapy and post-treatment CT as a result, PET-CT checks to be in administration first 1 week as a result, before treatment before treating
CT examination is the result is that 2018.7.21 inspection result.After treating 2 periods, patient's lesion reduces particularly evident, tumor markers
CEA, CA199, CA72.4 are also reduced to 26.97ng/ by entering 122.2ng/ml, 1871U/ml, 23.54U/ml before group respectively
Ml, 86.1U/ml, 7.92U/ml (Fig. 6, in every group of result, left side be treatment before, after right side is treatment).Patient in
2018.10.10 start the medication of the 3rd period, dosage is the same, in successive treatment tracking.
The result shows that patient, which is completed 2, treated and commented effect PR (partial response) in the period (2 months or so),
Lesion is reduced significantly, and is benefited from treatment obvious.
Two, the course of disease and treatment condition of patient two
Patient two: poplar * *, female
It is diagnosed the medium-low differentiation gland cancer of antrum, row radical-ability resection of gastric carcinoma in January, 2016.Postoperative pathological: distal end antrum
The medium-low differentiation gland cancer of lesser curvature side, postoperative pathological by stages: pT3N3b, immunohistochemistry show HER2 positive (3+).
It finds within 2 months 2016 right inguinal lymph nodes transfer, gives the oxaliplatin capecitabine chemotherapy (state of an illness successively
Progress), RC48-ADC treatment (disease progression), Irinotecan combine Herceptin (disease progression) multi-thread treatment.
The patient of in September, 2018 enters the clinical research of group inventor.In 2018.9.11 to being given during 2018.10.8 the 1st week
Phase medication, totally 28 days, specific medication are as follows: CDK4/6 inhibitor 100mg takes orally, once a day, continuous 3 weeks；HER2 inhibitor
400mg takes orally, once a day, continuous 4 weeks.The 2nd period drug therapy is given in 2018.10.9 to 2018.11.5, totally 28 days,
Specific medication is the same as the 1st period.2018.11.7 enhanced CT check is carried out, effect is commented to reduce SD (stable disease, tumor regression
About 20%).Fig. 7 is pretherapy and post-treatment CT as a result, Fig. 7 A is CT result (2018.9.9) before treating, and Fig. 7 B is CT result after treatment.
After treating 2 periods, patient's lesion reduce it is particularly evident, tumor markers CEA, CA199, CA72.4 also respectively by entering group before
5.49ng/ml, 250.1U/ml, 78.46U/ml are reduced to 1.92ng/ml, 14.32U/ml, 12.74U/ml (Fig. 8, every group of result
In, left side be treatment before, after right side is treatment).Patient starts the medication of the 3rd period in 2018.11.6, and dosage is the same, after
In continuous treatment tracking.
The result shows that patient is completed 2 cycle therapies and effect is commented to reduce SD, lesion is reduced significantly, benefits from treatment
Obviously.
Claims (9)
1.CDK4/6 inhibitor and HER2 inhibitor are preparing the application in composition；The composition is for treating the HER2 positive
Patients with gastric cancer.
2.CDK4/6 inhibitor and HER2 inhibitor are preparing the application in composition；The composition is for treating the HER2 positive
And drug resistant patients with gastric cancer.
3.CDK4/6 inhibitor and HER2 inhibitor are preparing the application in composition；The composition is for treating the HER2 positive
And the drug resistant patients with gastric cancer of HER2 inhibitor.
4.CDK4/6 inhibitor and HER2 inhibitor are preparing the application in composition；The composition is for treating gastric cancer trouble
Person.
5. the application as described in any in Claims 1-4, it is characterised in that: the active constituent of the composition is CDK4/6
Inhibitor and HER2 inhibitor.
6. a kind of composition, active constituent is CDK4/6 inhibitor and HER2 inhibitor；The composition is for treating HER2
Positive gastric carcinoma patient.
7. a kind of composition, active constituent is CDK4/6 inhibitor and HER2 inhibitor；The composition is for treating HER2
Positive and drug resistant patients with gastric cancer.
8. a kind of composition, active constituent is CDK4/6 inhibitor and HER2 inhibitor；The composition is for treating HER2
The positive and drug resistant patients with gastric cancer of HER2 inhibitor.
9. a kind of composition, active constituent is CDK4/6 inhibitor and HER2 inhibitor；The composition is for treating gastric cancer
Patient.
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| CN110840892A (en) * | 2018-08-21 | 2020-02-28 | 江苏恒瑞医药股份有限公司 | Use of a tyrosine kinase inhibitor in combination with a CDK4/6 inhibitor for the preparation of a medicament for the prevention or treatment of a neoplastic disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015134674A1 (en) * | 2014-03-04 | 2015-09-11 | The Regents Of The University Of California | Biomarkers of response to cyclin d-cdk4/6 targeted therapies in cancer |
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| WO2015134674A1 (en) * | 2014-03-04 | 2015-09-11 | The Regents Of The University Of California | Biomarkers of response to cyclin d-cdk4/6 targeted therapies in cancer |
Non-Patent Citations (2)
| Title |
|---|
| SHOM GOEL ET AL: "Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors", 《CANCER CELL》 * |
| 孙燕，姜藻: "胃癌分子靶向治疗的现状及研究进展", 《东南大学学报》 * |
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| CN110840892A (en) * | 2018-08-21 | 2020-02-28 | 江苏恒瑞医药股份有限公司 | Use of a tyrosine kinase inhibitor in combination with a CDK4/6 inhibitor for the preparation of a medicament for the prevention or treatment of a neoplastic disease |
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