|(84)||Designated Contracting States: |
|AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|(30)||Priority: ||28.03.2014 IT MI20140537|
|(43)||Date of publication of application: |
|01.02.2017 Bulletin 2017/05|
- Universita' degli Studi di Genova
16126 Genova (IT)
- L-Nutra Inc.
Plano, TX 75024 (US)
- BALLESTRERO, Alberto
I-16146 Genova (IT)
- CAFFA, Irene
I-17021 Alassio (SV) (IT)
- LONGO, Valter
Culver City, California 90232 (US)
- NENCIONI, Alessio
I-16132 Genova (IT)
- ODETTI, Patrizio
I-16128 Genova (IT)
- PATRONE, Franco
I-16129 Genova (IT)
|(74)||Representative: Ferreccio, Rinaldo |
|Botti & Ferrari S.p.A.
Via Cappellini, 11|
20124 Milano (IT)
|(56)||References cited: : |
| || |
- LAVIANO ALESSANDRO ET AL: "Toxicity in chemotherapy--when less is more.", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 366, no. 24, 14 June 2012 (2012-06-14), pages 2319-2320, XP008172000, ISSN: 1533-4406 cited in the application
- SAFDIE FERNANDO M ET AL: "Fasting and cancer treatment in humans: A case series report.", AGING, vol. 1, no. 12, December 2009 (2009-12), pages 1-20, XP002729596, ISSN: 1945-4589 cited in the application
- FERNANDO SAFDIE ET AL: "Fasting Enhances the Response of Glioma to Chemo- and Radiotherapy", PLOS ONE, vol. 7, no. 9, E44603, 11 September 2012 (2012-09-11), pages 1-9, XP055139410, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0044603 cited in the application
- E I HEATH ET AL: "A Phase I Study of the Pharmacokinetic and Safety Profiles of Oral Pazopanib With a High-Fat or Low-Fat Meal in Patients With Advanced Solid Tumors", CLINICAL PHARMACOLOGY & THERAPEUTICS, vol. 88, no. 6, 27 December 2010 (2010-12-27), pages 818-823, XP055139340, ISSN: 0009-9236, DOI: 10.1038/clpt.2010.199
- DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1992, BUJKO JACEK ET AL: "The effect of model diets with various fat and carbohydrate content on consumption of energy reserves during short-term starvation of laboratory animals", XP002742342, Database accession no. PREV199395030815 & POLISH JOURNAL OF FOOD AND NUTRITION SCIENCES, vol. 1, no. 3, 1992, pages 109-117, ISSN: 1230-0322
- BRANDHORST SEBASTIAN ET AL: "Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression", EXPERIMENTAL GERONTOLOGY, vol. 48, no. 10, 21 February 2013 (2013-02-21), pages 1120-1128, XP028704571, ISSN: 0531-5565, DOI: 10.1016/J.EXGER.2013.02.016
- F. L. Opdam ET AL: "Lapatinib for Advanced or Metastatic Breast Cancer", The Oncologist, vol. 17, no. 4, 1 April 2012 (2012-04-01), pages 536-542, XP055249889, US ISSN: 1083-7159, DOI: 10.1634/theoncologist.2011-0461
- Hwang-Phill Kim ET AL: "Lapatinib, a Dual EGFR and HER2 Tyrosine Kinase Inhibitor, Downregulates Thymidylate Synthase by Inhibiting the Nuclear Translocation of EGFR and HER2", PLoS ONE, vol. 4, no. 6, 16 June 2009 (2009-06-16), page e5933, XP055671574, DOI: 10.1371/journal.pone.0005933
- KONECNY GOTTFRIED E ET AL: "Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells", CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 66, no. 3, 1 February 2006 (2006-02-01), pages 1630-1639, XP002472825, ISSN: 0008-5472, DOI: 10.1158/0008-5472.CAN-05-1182
- Patrick Roberts: "Clinical use of crizotinib for the treatment of non-small cell lung cancer", Biologics: Targets and Therapy, 1 April 2013 (2013-04-01), page 91, XP055671566, DOI: 10.2147/BTT.S29026
|The file contains technical information submitted after the application was filed and not included in this specification|
The present invention concerns the technical field of the pharmaceutical industry.
In particular, the invention relates to compounds with tyrosine kinase inhibiting activity for use in the treatment of cancer in association with a defined dietetic regimen, as defined in more detail in the claims.
The invention is defined in the claims. Any subject-matter not encompassed by the claims does not form part of the invention.
Molecularly targeted agents that interfere with the tyrosine kinase activity of their target are now the mainstay of treatment in several types of cancer in advanced stages. Gefitinib, erlotinib and afatinib (EGFR tyrosine kinase inhibitors - TKIs) have changed the natural history of advanced non-small cell lung cancer -NSCLC- with mutated EGFR with a proven superiority over standard platinum-based chemotherapy and objective response rates observed in 60-80% of the patients (1).
The anaplastic lymphoma kinase (ALK) inhibitor crizotinib is successfully employed in NSCLC with EML4-ALK translocations (2), while lapatinib (a dual HER2/EGFR TKI), and regorafenib (a multitarget TKI) are approved for treating HER2+ metastatic breast cancer (BC) and metastatic colorectal cancer (CRC), respectively (3-5).
Despite their success, a major limitation of these agents is that their efficacy is frequently short lived with the result that virtually all patients progress and ultimately succumb to their disease (1, 4, 5). Thus, strategies that help increase the efficacy of these agents making them more powerful and capable of more effectively eradicating cancer cells are warranted.
It is also known from a number of studies that short courses of starvation (short-term starvation, STS) sensitize cancer cells to DNA damaging agents, including chemotherapeutics and radiotherapy (6-8). This effect essentially reflects the inability of malignant cells to adapt to nutrient deprivation, primarily due to the aberrant activation of growth promoting signaling cascades. Vice versa, non-transformed tissues may even benefit from STS by reverting to a self-protection mode characterized by reduced cell growth, increased sirtuin activity, and autophagy activation, thus becoming more resistant to genotoxic stress and able to tolerate doses of chemotherapeutics that would otherwise be lethal for non-starved cells (9).
The discovery that STS increases the efficacy of chemotherapy in cancer cells, while at the same time shielding healthy cells from its toxicity, has recently attracted strong attention to this approach amongst physicians(10) and patients, and several pilot trials are currently exploring STS in combination with chemotherapy in humans (including studies performed at the University of Genoa, USC Norris Comprehensive Cancer Center, Mayo Clinic, and at the University of Leiden; NCT01304251, NCT01175837, NCT00936364, NCT01175837).
However, combining fasting (or reduced-calorie diets) with chemotherapy presents important limitations. In the first place, there is a strong concern among oncologists that adding starvation to debilitating therapies, such as chemotherapy or radiotherapy, might lead to unacceptable weight losses. Second, chemotherapy and radiotherapy are frequently administered in combination with corticosteroids (to counter side effects, such as nausea, and allergic reactions) and this may prevent some of the metabolic adaptations to starvation (i.e. hypoglicemia) which are thought to underlie its beneficial effects in cancer patients. Thus, the benefits of fasting (or reduced-calorie diets) could be better exploited in combination with more modern anticancer agents, such as tyrosine kinase inhibitors, which have less side effects and act through mechanisms that are totally different from those which chemotherapeutics are based on.
Nevertheless, no reliable forecasts can be made on the effects that fasting (or reduced-calorie diets) may have on the efficacy of an anticancer therapy based on tyrosine kinase inhibitors.
For these reasons, the research carried out by the Applicant focused on the investigation of the possible interaction between starvation or reduced-calorie diets and an anticancer therapy based on tyrosine kinase inhibitors.
The present invention is the result of the above research activity.
 US 2008/166427
discloses a method for potentiating the antitumor effect of the antimetabolite tegafur, while reducing gastrointestinal toxicity, which method comprises administering, together with tegafur, a dihydropyrimidine dehydrogenase inhibitor in an amount effective for potentiating the antitumor effect and an oxonic acid in an amount effective for suppressing gastrointestinal toxicity, under fasting conditions. Optionally, a chemotherapy agent can additionally be administered and such agent can be i.a. gefitinib, a TKI. A potentiating effect on the antitumor acitivity of tegafur in fasting conditions is only disclosed in connection with the dihydropyrimidine dehydrogenase inhibitor and not with gefitinib. The fasting conditions are defined as fasting at least one hour before a meal or after a meal and preferably 1-2 hours before or after a meal.
Summary of the invention
In an aspect thereof, the present invention relates to a tyrosine kinase inhibitor (TKI) for use in a method for the treatment of non-small cell lung cancer or breast cancer in a human patient, the method comprising subjecting said patient to reduced caloric intake for a period of 24-190 hours while said patient is being treated with said tyrosine kinase inhibitor, wherein said reduced caloric intake corresponds to less than 300 kcal/day and wherein: when the patient is affected by non-small cell lung cancer, the TKI is Crizotinib, and when the patient is affected by breast cancer, the TKI is Lapatinib.
By reduced caloric intake it is hereby meant, as far as encompassed by the claims, a daily caloric intake reduced by 10-100%, preferably by 50-100%, more preferably by 85-100%, with respect to the regular caloric intake, including total starvation.
The subject's regular caloric intake is the number of kcal that the subject consumes to maintain his/her weight. The subject's normal caloric intake may be estimated by interviewing the subject or by consideration of a subject's weight. As a rough guide, subject's normal caloric intake is on average 2600 kcal/day for men and 1850 kcal/day for women.Preferably, when the daily caloric intake is reduced by 10-85%, the patient is fed with foods with a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and carbohydrates (≥ 50% of calories coming from fat). This because a diet based on such foods has beneficial effects that are similar to those of starvation (16).
Preferably said period of reduced caloric intake ranges from 48 to 150 hours, and most preferably it is of about 120 hours.
The tyrosine kinase inhibitor (TKI) is is Crizotinib when the patient is affected by non-small cell lung cancer, and Lapatinib when the patient is affected by breast cancer.
As used herein, "cancer" refers to a disease or disorder characterized by uncontrolled division of cells and the ability of these cells to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis. Examples of cancers include, but are not limited to, primary cancer, metastatic cancer, carcinoma, lymphoma, leukemia, sarcoma, mesothelioma, glioma, germinoma, choriocarcinoma, prostate cancer, lung cancer, breast cancer, colorectal cancer, gastrointestinal cancer, bladder cancer, pancreatic cancer, endometrial cancer, ovarian cancer, melanoma, brain cancer, testicular cancer, kidney cancer, skin cancer, thyroid cancer, head and neck cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, rectal cancer, myeloma, neuroblastoma, pheochromocytoma, and retinoblastoma.
In the context of the present invention, the cancer is selected from non-small cell lung cancer (NSCLC) and breast cancer.
The above-mentioned period of reduced caloric intake with concurrent administration of the tyrosine kinase inhibitor to the patient can be repeated one or more times after respective periods of 5-60 days, during which the patient is given the tyrosine kinase inhibitor while following a diet involving a regular caloric intake.
The above-mentioned reduced calorie intake regimen corresponds to less than 300 kcal/day, preferably 100-200 Kcal/day.
Such reduced caloric intake can be obtained by means of dietetic foods with reduced caloric and protein content but containing all necessary micronutrients to prevent malnutrition.
In another aspect, the present invention relates to a pharmaceutical composition comprising a tyrosine kinase inhibitor as defined above and a pharmaceutically acceptable carrier for use in the method for the treatment of cancer in a patient as defined in the claims.
As it will become clear from the experimental results reported in the following sections, it has unexpectedly been found that starvation, in particular STS, and also a reduced caloric intake for periods of 24-72, positively affect the efficacy of a concurrent anticancer treatment with a tyrosine kinase inhibitor.
Differently from what happened with the previously known treatments associating STS with chemotherapy or radiotherapy, which generally required the administration of a corticosteroid in order to counter the side effects (i.e. nausea) and allergic reactions caused by chemotherapy and radiotherapy, the method according to the present invention does not require the administration of corticosteroids, because tyrosine kinase inhibitors do not display the severe side effects of chemotherapy or radiotherapy.
This is quite a significant advantage over the above-mentioned known treatments, because the metabolic adaptations to starving (e.g. hypoglycemia), which are beneficial in terms of response by the tumor cells, are not prevented or hindered by a concomitant administration of corticosteroids.
The compounds and compositions according to the invention may be administered with any available and efficient delivery system, comprising oral, buccal, parenteral, inhalatory routes, topical application, by injection, by transdermic or rectal route (for ex. by means of suppositories) in dosage unit formulations containing conventional, pharmaceutically acceptable and non-toxic carriers, adjuvants and vehicles. The administration by parenteral route comprises subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques.
The solid dosage forms for the administration by oral route comprise, for example, capsules, tablets, powders, granules and gels. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as, for example, sucrose, lactose or starch. These dosage forms normally also comprise additional substances different from the inert diluents, such as, for example, lubricating agents like magnesium stearate.
The injectable preparations, for example aqueous or oily sterile injectable solutions or suspensions, may be formulated according to the known technique and by optionally using appropriate dispersing, wetting and/or suspending agents.
The average daily dosage of the compounds according to the present invention depends on many factors, such as, for example, the seriousness of the disease and the conditions of the patient (age, weight, sex): The dose may generally vary from 1 mg to 1500 mg per day of compound according to the invention, optionally divided into more administrations.
The present invention will be further described with reference to the appended drawings and to certain embodiments, which are provided here below by way of illustration.
Brief description of the drawings
Fig. 1A is a bar graph showing the respective effects of short term starvation (STS), Crizotinib and STS + Crizotinib on the viability of H3122 non-small cell lung cancer cells (NSCLC).
Fig. 1B is a bar graph showing the respective effects of short term starvation (STS), TAE684 and STS + TAE684 on the viability of H3122 NSCLC cells.
Fig. 1C is a photograph showing the effects of short term starvation (STS), Crizotinib and STS + Crizotinib on H3122 (NSCLC) cells plated in Petri dishes in DMEM medium.
Fig. 1D is a histogram showing the respective effects of short term starvation (STS), Crizotinib and STS + Crizotinib on the viability of A549 NSCLC cells (which do not harbor an EML4-ALK translocation and, therefore, are normally insensitive to crizotinib).
Fig. 1E is an immunoblotting showing the levels of phospho-ERK and total ERK in cell lysates from H3122 cells subjected to, respectively, STS, treatment with Crizotinib and STS + treatment with Crizotinib.
Fig. 2A is a diagram showing the size (mass volume) of H3122 xenografts in mice subjected to, respectively, STS; Crizotinib treatment; STS + Crizotinib treatment; no treatment (control). *p<0.05.
Fig. 2B is a diagram showing the body weight of mice subjected to, respectively, STS; Crizotinib treatment; STS + Crizotinib treatment; no treatment (control).
Fig. 3A is a histogram showing the respective effects of short term starvation (STS), Lapatinib and STS + Lapatinib on the viability of SKBR3 cells (HER2+ breast cancer).
Fig. 3B is a histogram showing the respective effects of short term starvation (STS), Lapatinib and STS + Lapatinib on the viability of BT474 cells (HER2+ breast cancer).
Fig. 3C is a photograph showing the effects of short term starvation (STS), Lapatinib and STS + Lapatinib on BT474 cells plated in Petri dishes in DMEM medium.
Fig. 3D is a histogram showing the respective effects of short term starvation (STS), CP724714 (an HER tyrosine kinase inhibitor) and STS + CP724714 on the viability of SKBR3 cells.
Fig. 3E is a histogram showing the respective effects of short term starvation (STS), Lapatinib and STS + Lapatinib on MCF7 cells (which do not harbor a HER2 amplification and, therefore, are normally insensitive to lapatinib).
Fig. 4A is an immunoblotting showing the levels of phosphor-Akt, total Akt, phospho-ERK and total ERK in cell lysates from SKBR3 cells subjected to, respectively, STS, treatment with Lapatinib and STS + treatment with Lapatinib.
Fig. 4B is an immunoblotting showing the levels of phosphor-Akt, total Akt, phospho-ERK and total ERK in cell lysates from BT474 cells subjected to, respectively, STS, treatment with Lapatinib and STS + treatment with Lapatinib.
Fig. 4C is a flow cytometry analysis (forward scatter, FSC; 10.000 events per cell sample) of BT474 subjected to, respectively, STS, treatment with Lapatinib and STS + treatment with Lapatinib.
The Applicants performed several experiments to assess whether conditions that mimic the metabolic effects of starvation in vitro (cell culture in the presence of low serum (1% FBS) and low glucose (0.5 g/L) sensitize cancer cells to two TKIs, Crizotinib and Lapatinib, that are commonly used in EML4-ALK+ NSCLC and in HER2+ BC (breast cancer cells), respectively.
With reference to Figs. 1A and 1B, 3×103
H3122 cells were plated in 96 well plates in regular DMEM medium containing 10% FBS. 24h later, the cell medium was removed and cells were incubated for 24h either in the same medium (CTR) or in low-glucose (0.5 g/L) DMEM medium containing 1 % FBS (STS). 24h later cells were treated or not with the indicated concentrations of Crizotinib or TAE382 (TAE). 72h later, viability was measured with sulforodhamine B-based assays.
With reference to Fig. 1C, 105
H3122 cells were plated in 60mm Petri dishes in regular DMEM medium. 24h later, the cell medium was removed and cells were incubated for 24h either in regular medium (CTR) or in STS conditions. 24h later 400 nM Crizotinib was added (or not) to the cells. 5 days later, the cell medium was removed and the cells were cultured for two additional days in regular DMEM medium. 48h later, the plates were stained with sulforodhamine B and photographed.
With reference to Fig. 1D, 3×103
A549 cells were plated in 96 well plates and treated with Crizotinib in the presence or absence of STS, as in the experiments of Figs. 1A and 1B, before viability was measured in sulforodhamine B-based assays.
With reference to Fig. 1E, 105
H3122 cells were plated in 6 well plates in regular DMEM medium containing 10% FBS. 24h later, the cell medium was removed and cells were incubated for 24h either in the same medium (CTR) or in low-glucose (0.5 g/L) DMEM containing 1 % FBS (STS). 24h later cells were treated or not with 400 nM Crizotinib. After 24h, cell were used for cell lysate preparation and phospho-ERK (Thr202/Tyr204), and total ERK levels were detected by immunoblotting.
Having regard to the above experiments, it can be concluded that in H3122 NSCLC cells (which carry the EML4-ALK translocation), STS conditions strongly potentiated the activity of Crizotinib and of TAE684, an unrelated ALK inhibitor (Figure 1A-C), leading to a virtual complete killing of NSCLC cells in the presence of 400 nM Crizotinib (Figure 1C). Notably, A549 NSCLC cells, which do not have an EML4-ALK translocation, were insensitive to Crizotinib and STS did not increase the activity of the TKI in this cell line (Figure 1D). Thus, STS did not simply increase the cytotoxic activity of Crizotinib, but instead it allowed to retain its specificity for cancer cells with aberrant ALK activity. Notably when administered to starved cells, Crizotinib was more effective at blocking signaling through the MAPK pathway (ERK1/2 phosphorylation) than it was in cells cultured in standard conditions (Figure IE), which suggests a plausible mechanism for the observed potentiation of Crizotinib efficacy through STS.
In line with this hypothesis is the observation that H3122 cells engineered to overexpress HRAS or HRAS V12 were resistant to crizotinib, STS-mimicking conditions or their combination (not shown), which is consistent with inhibition of the MAPK pathway playing a key role in the anticancer activity of these treatments.
With reference to Fig. 2A, six- to eight-week-old BALB/c athymic mice (nu+/nu+) were injected s.c. with 5×106
H3122 cells. When tumors became palpable, mouse were randomly assigned to one of four arms (six mice per treatment arm): control - normal diet (-); Crizotinib - normal diet with 3 cycles of Crizotinib (25 mg/kg/day via oral gavage for 5 days a week, Mon-Fri); STS [fasting (water only) for 48h (Sun-Tue) for three cycles at 1-week intervals]; STS+Crizotinib. Tumor size was measured daily and tumor volume was calculated using the formula: tumor volume= (w2
× W) × n/6, where "w" and "W" are "minor side" and "major side" (in mm), respectively . At the end of treatment, mice were euthanized and tumor masses were excised and weighted (see Fig. 2B). Mouse weight was also monitored daily.
From the above reported experiments it can be observed that, in vivo, both fasting cycles and Crizotinib effectively reduced the growth of H3122 xenografts with no difference in terms of efficacy between the two approaches, but the combination Crizotinib+fasting was more active than either type of treatment alone (*: p<0.05; **: p<0.01; ***: p<0.001; Figure 2A-B). Fasted mice exhibited transient weight losses, but fully recovered their weight between one cycle and the next (Figure 2B). Clearly, this data indicates the potential of STS conditions to make ALK inhibitors more effective with possible strong benefits for the patients.
With reference to Figs. 3A and 3B, 3×103
SKBR3 (Fig. 3A) or BT474 (Fig. 3B) cells/well were plated in 96 well plates in regular DMEM medium containing 10% FBS and 2,5 g/L glucose. 24 h later, the cell medium was removed and cells were incubated for 24h either in the same medium (CTR) or in low-glucose (0.5 g/L) DMEM medium containing 1% FBS (STS). 24h later cells were treated or not with 100 nM Lapatinib. 72h later, viability was measured in sulforodhamine B-based assays.
With reference to Fig. 3C, 4×105
BT474 cells were plated in 60mm Petri dishes in regular DMEM medium. 24h later, the cell medium was removed and cells were incubated for 24h either in regular medium (CTR) or in STS conditions. 24h later 100 nM Lapatinib was added (or not) to the cells. 5 days later, the cell medium was removed and the cells were cultured for additional two days in regular DMEM medium. 48h later, the plates were stained with sulforodhamine B and photographed.
With reference to Figs. 3D and 3E, BT474 or MCF7 cells were plated as detailed with regard to Figs. 3A and 3B, treated with 100 nM CP724714 (Fig. 3D) or Lapatinib (Fig. 3E) with or without STS conditions as detailed with respect to Figs. 3A and 3B before viability was detected.
With reference to Figs. 4A-C, 105
SKBR3 (Fig. 4A) or BT474 (Fig. 4B) cells were plated in 6 well plates in regular DMEM medium containing 10% FBS. 24h later, the cell medium was removed and cells were incubated for 24h either in the same medium (CTR) or in low-glucose (0.5 g/L) DMEM medium containing 1% FBS (STS). 24h later cells were treated or not with 100 nM Lapatinib. After 24h, cell were either used for cell lysate preparation or for flow cytometry assays. Cell lysates were used for phospho-AKT (Ser473), total AKT, phospho-ERK (Thr202/Tyr204), and total ERK level detection by immunoblotting (Figs. 4A and 4B). Flow cytometry (with a FACS Calibur, BD) was used to estimate cell size (FSC) by acquiring 10.000 events per cell sample (Fig. 4C).
From the experiments of Figs. 3A-E, it can be noted that, in the case of Lapatinib, as shown in Figures 3A and 3B, both BT474 and SKBR3 (HER2+ BC cell lines) cells were strongly sensitized to therapeutic concentrations of this agent by STS conditions (see also Figure 3C).
Similar results were obtained using an unrelated HER2 TK inhibitor, CP724714 (13) (Figure 3D), thus confirming that the observed cooperation between STS and Lapatinib was due to inhibition of HER2 TK activity. As expected (12, 14), MCF7 cells (Fig. 3E), which do not harbor HER2 amplification, were insensitive to Lapatinib and STS failed to enhance the activity of this TKI in this cell line, again indicating that STS-mimicking conditions potentiate the TKI activity without compromising its specificity. At the molecular level, cells treated with Lapatinib in STS-mimicking conditions exhibited a more pronounced inhibition of AKT and ERK1/2 signaling than cells treated with Lapatinib alone. Given the importance of these signaling cascades in the survival of HER2+ BC (15), these findings could well justify the observed cooperation between the two types of interventions (Figure 4A, B).
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Tyrosinkinase-Inhibitor (TKI) zur Verwendung in einem Verfahren zur Behandlung von nicht-kleinzelligem Lungenkrebs oder Brustkrebs bei einem menschlichen Patienten, wobei das Verfahren aufweist, dass der Patient für einen Zeitraum von 24-190 Stunden einer verringerten Kalorienaufnahme unterzogen wird, während der Patient mit dem Tyrosinkinase-Inhibitor behandelt wird, wobei die verringerte Kalorienaufnahme weniger als 300 kcal / Tag entspricht und wobei:
der TKI Crizotinib ist, wenn der Patient von nicht-kleinzelligem Lungenkrebs befallen ist und
der TKI Lapatinib ist, wenn der Patient von Brustkrebs befallen ist.
2. Tyrosinkinase-Inhibitor zur Verwendung nach Anspruch 1, wobei der Patient mit Nahrungsmitteln mit einem hohen Gehalt an einfach ungesättigten und mehrfach ungesättigten Fetten und einem verringerten Gehalt an Proteinen und Kohlehydraten ernäht wird, wobei ≥ 50% der Kalorien von den Fetten stammen.
3. Tyrosinkinase-Inhibitor zur Verwendung nach einem der Ansprüche 1 und 2, wobei der Zeitraum der verringerten Kalorienaufnahme 48-150 Stunden, bevorzugt etwa 120 Stunden beträgt.
4. Tyrosinkinase-Inhibitor zur Verwendung nach einem der Ansprüche 1 bis 3, wobei der Zeitraum der verringerten Kalorienaufnahme mit gleichzeitiger Verabreichung des Tyrosinkinase-Inhibitors an den Patienten einmal oder mehrmals jeweils nach Zeiträumen von 5 bis 60 Tagen, während denen dem Patienten der Tyrosinkinase-Inhibitor verabreicht wird, während er sich an einen Speiseplan hält, der eine normale Kalorienaufnahme beinhaltet, wiederholt wird.
5. Tyrosinkinase-Inhibitor zur Verwendung nach einem der Ansprüche 1 bis 4, wobei die verringerte Kalorienaufnahme 100-200 kcal / Tag entspricht.
6. Tyrosinkinase-Inhibitor zur Verwendung nach Anspruch 5, wobei die verringerte Kalorienaufnahme erreicht wird durch Fasten oder mittels diätetischer Nahrungsmittel mit verringertem Kaloriengehalt und / oder Proteingehalt, die aber alle erforderlichen Mikronährstoffe enthalten, um eine Fehlernährung zu verhindern.
7. Pharmazeutische Zusammensetzung aufweisend einen Tyrosinkinase-Inhibitor wie in Anspruch 1 definiert, zur Verwendung wie in einem der Ansprüche 1 bis 6 definiert.