WO2008140751A1 - Human leiosarcoma and non small cell lung cancer lung xenograft models - Google Patents

Human leiosarcoma and non small cell lung cancer lung xenograft models Download PDF

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Publication number
WO2008140751A1
WO2008140751A1 PCT/US2008/005936 US2008005936W WO2008140751A1 WO 2008140751 A1 WO2008140751 A1 WO 2008140751A1 US 2008005936 W US2008005936 W US 2008005936W WO 2008140751 A1 WO2008140751 A1 WO 2008140751A1
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xenograft
mouse
model
tumor
treatment
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PCT/US2008/005936
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French (fr)
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David Sidransky
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Champions Biotechnology, Inc.
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/027—New breeds of vertebrates
    • A01K67/0271—Chimeric animals, e.g. comprising exogenous cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0331—Animal model for proliferative diseases
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • Soft tissue sarcomas are malignant tumors that originate from fat, muscle, nerve, blood vessel, and fibrous or deep skin tissues and can occur in most parts of the body.
  • Leiomyosarcoma (LMS) is a malignant tumor originating from smooth muscle tissue, most often the retroperitoneum, internal organs and blood vessels. While occurrence of LMS is quite rare, current therapies are limited and treatment potential for newly approved agents and novel combination regimens are largely unknown, primarily due to lack of evaluable models for each disease.
  • NSCLC non small cell lung cancer
  • squamous cell carcinoma large cell carcinoma
  • adenocarcinoma adenocarcinoma
  • a human leiomyosarcoma xenograft model is provided that is capable of stable propagation in immunodeficient mice.
  • the model is useful for P-9857-PC
  • the model demonstrates specificity towards various chemotherapeutic agents and combinations thereof.
  • a method for identifying an optimal chemotherapeutic regimen for a human leiomyosarcoma tumor in a patient by the steps of (1) establishing a xenograft of the tumor in immunodeficient mice, (2) confirming the phenotypic stability of the tumor, and (3) evaluating the effect on tumor growth inhibition by at least one chemotherapeutic regimen, such as by a single agent or at least one combination of chemotherapeutic agents, wherein an effective chemotherapeutic regimen in the xenograft model identifies a regimen useful for treatment of the disease in the patient.
  • the optimal schedule and dose of chemotherapeutic agent administration is determined in the model then applied to the patient.
  • a method for assessing the effect of a composition or treatment on human leiomyosarcoma comprising: a) providing an immune deficient mouse comprising a xenograft of human leiomyosarcoma, wherein the xenograft is allowed to grow for a sufficient time to permit the detection of a tumor; b) subjecting the mouse to the composition or treatment; and, c) determining the effect of the composition or treatment on the growth of the xenograft in the mouse.
  • the xenograft is a subcutaneous xenograft.
  • the immune deficient mouse is a nude mouse.
  • an immunodeficient mouse having a xenograft of a human leiomyosarcoma.
  • the xenograft is subcutaneous.
  • the immunodeficient mouse is a nude mouse.
  • a human non small cell lung cancer xenograft model is provided that is capable of stable propagation in immunodeficient mice.
  • the model is useful for determining sensitivity of tumor growth to single or combinations of chemotherapeutic agents administered to the mouse.
  • the model demonstrates specificity towards various chemotherapeutic agents and combinations thereof.
  • a method for identifying an optimal chemotherapeutic regimen for a human non small cell lung cancer in a patient by the steps of (1 ) establishing a xenograft of P-9857-PC
  • the tumor in immunodef ⁇ cient mice, (2) confirming the phenotypic stability of the tumor, and (3) evaluating the effect on tumor growth inhibition by at least one chemotherapeutic regimen, such as by a single agent or at least one combination of chemotherapeutic agents, wherein an effective chemotherapeutic regimen in the xenograft model identifies a regimen useful for treatment of the disease in the patient.
  • the optimal schedule and dose of chemotherapeutic agent administration is determined in the model then applied to the patient.
  • a method for assessing the effect of a composition or treatment on human non small cell lung cancer comprising: a) providing an immune deficient mouse comprising a xenograft of human non small cell lung cancer, wherein the xenograft is allowed to grow for a sufficient time to permit the detection of a tumor; b) subjecting the mouse to the composition or treatment; and, c) determining the effect of the composition or treatment on the growth of the xenograft in the mouse.
  • the xenograft is a subcutaneous xenograft.
  • the immune deficient mouse is a nude mouse.
  • an immunodeficient mouse having a xenograft of a human non small cell lung cancer.
  • the xenograft is subcutaneous.
  • the immunodeficient mouse is a nude mouse.
  • FIG. 1 A-B show the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents:
  • IA Combination of irinotecan + bevacizumab, bortezomib + bevacizumab, sirolimus + bevacizumab, and gemcitabine + bevacizumab.
  • IB Control, temozolomide, and temozolomide + sorafenib.
  • FIG. 2 shows the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: control, sunitinib, sunitinib + docetaxel, sunitinib + docetaxel + bevacizumab, sunitinib + bevacizumab.
  • FIG. 3 A-D show the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: 3A.
  • FIG. 4 show the result of a chemotherapy sensitivity study in the non small cell lung cancer xenograft model using control, sorafenib + bevacizumab (AVASTIN), sorafenib + bevacizumab + irinotecan, etoposide + cisplatin + bevacizumab, sunitinib + bevacizumab, oxaliplatin + Alimta, and rapamune + TARCEVA.
  • samples of a patient's LMS or NSCLC tumor can be xenografted into immunodeficient mice to provide a means for identifying the optimal agent(s) for treatment.
  • a xenotransplant model of LMS or NSCLC can be established to provide a method for assessing various chemotherapeutic agents, or combinations thereof, dosing regiments and variations thereof, generally on these types of cancer.
  • LMS tumors were removed from patients and fragments xenografted into male CD-I nude mice. Tumors were propagated and amplified until growth was stable and the take rate was >80%; molecular profiling was then performed on each tumor to establish baseline levels of relevant proteins and signaling molecules. Following establishment, these models were evaluated for sensitivity towards a panel of single agent and combination therapies, to identify parameters of inhibition: tumor growth inhibition (TGI) and the tumor growth delay (TGD). As will be shown in the examples below, treatment with bevacizumab potentiated the efficacy of other tested regimens. Impressive growth inhibition was found with ABI-007 in P-9857-PC
  • the nude mouse LMS and NSCLC models permit evaluation of single or combination therapies using approved or experimental therapeutic agents.
  • Non-limiting examples of such agents include the following agents.
  • Docetaxel (TAXOTERE) is a member of the taxane class of chemotherapy drugs, and is a semi-synthetic analogue of paclitaxel (Taxol®), an extract from the rare Pacific yew tree Taxus brevifolia.
  • Sorafenib (NEXAVAR) is a small molecular inhibitor of Raf kinase, PDGF (platelet- derived growth factor) and VEGF receptor kinase.
  • Sunitinib is a small molecule receptor tyrosine kinase inhibitor.
  • ABI-007 belongs to the family of drugs called mitotic inhibitors. It is also called nanoparticle paclitaxel, protein-bound paclitaxel, paclitaxel (Albumin-Stabilized Nanoparticle Formulation), and Abraxane.
  • Paclitaxel TAXOL
  • Bevacizumab AVASTIN
  • Bevacizumab is a monoclonal antibody that works by attaching to and inhibiting the action of vascular endothelial growth factor (VEGF) in laboratory experiments.
  • VEGF vascular endothelial growth factor
  • Pemetrexed is a new drug used for malignant pleural mesothelioma, and non-small cell lung cancer.
  • Sirolimus RAPAMUNE
  • TARCEVA erlotinib
  • Tarceva is a small molecule human epidermal growth factor type 1/epidermal growth factor receptor (HER1/EGFR) inhibitor.
  • Bortezomib VELCADE
  • gemcitabine GEMZAR
  • CAMPTO irinotecan
  • MITOXANA ifosfamide
  • FLUDARA fludarabine
  • LMS 01 is a leiomyosarcoma originating from a 55 year old Caucasian female.
  • FIG. 1 A-B show the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents:
  • IA Combination of irinotecan + bevacizumab, bortezomib + bevacizumab, sirolimus + bevacizumab, and gemcitabine + bevacizumab.
  • IB Control, temozolomide, and temozolomide + sorafenib.
  • FIG. 2 shows the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: control, sunitinib, sunitinib + docetaxel, sunitinib + docetaxel + bevacizumab, sunitinib + bevacizumab.
  • control sunitinib, sunitinib + docetaxel
  • sunitinib + bevacizumab The data show that combination with docetaxel did not provide a benefit.
  • Figs. 3 A-D The data collected over time is shown in Figs. 3 A-D. Treatment with some combination therapies was sufficient to produce extended tumor growth inhibition in each study. Treatment with bevacizumab potentiated the effect of most tested regimens while docetaxel did not provide a benefit in these studies. Comparable TGI effects were noted with sorafenib or sunitinib combination therapies. Impressive tumor growth inhibition and partial/complete responses were reported with ABI-007 in combination with bevacizumab; paclitaxel was ineffective towards this model
  • Tumor tissue fragments from a non-small cell lung cancer from a 50 year old male were implanted subcutaneously into male CD-I nude mice by trocar. When tumors reached approximately 100 mm 3 , animals were pair-matched by tumor volume into treatment and control groups and dosing initiated (Day 1). Mice were weighed and tumor measurements taken twice weekly by Vernier caliper. P-9857-PC
  • FIG. 4 shows the result of a chemotherapy sensitivity study in the non small cell lung cancer xenograft model using control, sorafenib + bevacizumab (Avastin), sorafenib + bevacizumab + irinotecan, etoposide + carboplatin + bevacizumab, sunitinib + bevacizumab, oxaliplatin + Alimta, and rapamune + Tarceva.
  • sorafenib and bevacizumab Avastin
  • sorafenib, bevacizumab and irinotecan, or etoposide, cisplatin and bevacizumab showed significant inhibition of tumor growth.

Abstract

The invention provides immunodeficient mice having a xenograft of either human leiomyosarcoma or non-small cell lung cancer, and uses thereof.

Description

P-9857-PC
HUMAN LEIOSARCOMA AND NON SMALL CELL LUNG CANCER LUNG
XENOGRAFT MODELS
BACKGROUND
[0001] Soft tissue sarcomas are malignant tumors that originate from fat, muscle, nerve, blood vessel, and fibrous or deep skin tissues and can occur in most parts of the body. Leiomyosarcoma (LMS) is a malignant tumor originating from smooth muscle tissue, most often the retroperitoneum, internal organs and blood vessels. While occurrence of LMS is quite rare, current therapies are limited and treatment potential for newly approved agents and novel combination regimens are largely unknown, primarily due to lack of evaluable models for each disease.
[0002] On the other hand, non small cell lung cancer (NSCLC) is more common, accounting for the majority of the 164,000 new lung cancer patients annually. NSCLC comprises three main types of cancer: squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar. Patients with resectable disease may be cured by surgery or surgery with adjuvant chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced, unresectable disease may have long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy. Animal models of the disease in general, and of a particular patient's tumor, would be invaluable in identifying potentially active chemotherapeutic agents as well as personalizing treatments.
SUMMARY
[0003] In one embodiment, a human leiomyosarcoma xenograft model is provided that is capable of stable propagation in immunodeficient mice. In a further embodiment, the model is useful for P-9857-PC
determining sensitivity of tumor growth to single or combinations of chemotherapeutic agents administered to the mouse. In another embodiment, the model demonstrates specificity towards various chemotherapeutic agents and combinations thereof.
[0004] In another embodiment, a method is provided for identifying an optimal chemotherapeutic regimen for a human leiomyosarcoma tumor in a patient by the steps of (1) establishing a xenograft of the tumor in immunodeficient mice, (2) confirming the phenotypic stability of the tumor, and (3) evaluating the effect on tumor growth inhibition by at least one chemotherapeutic regimen, such as by a single agent or at least one combination of chemotherapeutic agents, wherein an effective chemotherapeutic regimen in the xenograft model identifies a regimen useful for treatment of the disease in the patient. In another embodiment, the optimal schedule and dose of chemotherapeutic agent administration is determined in the model then applied to the patient.
[0005] In another embodiment, a method is provided for assessing the effect of a composition or treatment on human leiomyosarcoma, comprising: a) providing an immune deficient mouse comprising a xenograft of human leiomyosarcoma, wherein the xenograft is allowed to grow for a sufficient time to permit the detection of a tumor; b) subjecting the mouse to the composition or treatment; and, c) determining the effect of the composition or treatment on the growth of the xenograft in the mouse. In another embodiment, the xenograft is a subcutaneous xenograft. In another embodiment, the immune deficient mouse is a nude mouse.
[0006] In another embodiment, an immunodeficient mouse is provided having a xenograft of a human leiomyosarcoma. In a further embodiment, the xenograft is subcutaneous. In another embodiment, the immunodeficient mouse is a nude mouse.
[0007] In another embodiment, a human non small cell lung cancer xenograft model is provided that is capable of stable propagation in immunodeficient mice. In a further embodiment, the model is useful for determining sensitivity of tumor growth to single or combinations of chemotherapeutic agents administered to the mouse. In another embodiment, the model demonstrates specificity towards various chemotherapeutic agents and combinations thereof.
[0008] In yet another embodiment, a method is provided for identifying an optimal chemotherapeutic regimen for a human non small cell lung cancer in a patient by the steps of (1 ) establishing a xenograft of P-9857-PC
the tumor in immunodefϊcient mice, (2) confirming the phenotypic stability of the tumor, and (3) evaluating the effect on tumor growth inhibition by at least one chemotherapeutic regimen, such as by a single agent or at least one combination of chemotherapeutic agents, wherein an effective chemotherapeutic regimen in the xenograft model identifies a regimen useful for treatment of the disease in the patient. In another embodiment, the optimal schedule and dose of chemotherapeutic agent administration is determined in the model then applied to the patient.
[0009] In another embodiment, a method is provided for assessing the effect of a composition or treatment on human non small cell lung cancer, comprising: a) providing an immune deficient mouse comprising a xenograft of human non small cell lung cancer, wherein the xenograft is allowed to grow for a sufficient time to permit the detection of a tumor; b) subjecting the mouse to the composition or treatment; and, c) determining the effect of the composition or treatment on the growth of the xenograft in the mouse. In another embodiment, the xenograft is a subcutaneous xenograft. In another embodiment, the immune deficient mouse is a nude mouse.
[00010] In another embodiment, an immunodeficient mouse is provided having a xenograft of a human non small cell lung cancer. In a further embodiment, the xenograft is subcutaneous. In another embodiment, the immunodeficient mouse is a nude mouse.
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0001 1 ] Fig. 1 A-B show the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: IA. Combination of irinotecan + bevacizumab, bortezomib + bevacizumab, sirolimus + bevacizumab, and gemcitabine + bevacizumab. IB. Control, temozolomide, and temozolomide + sorafenib.
[00012] Fig. 2 shows the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: control, sunitinib, sunitinib + docetaxel, sunitinib + docetaxel + bevacizumab, sunitinib + bevacizumab.
[00013] Fig. 3 A-D show the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: 3A. Gemcitabine + docetaxel + bevacizumab, gemcitabine + docetaxel + bevacizumab + irinotecan, gemcitabine + docetaxel + P-9857-PC
bevacizumab + temozolomide, gemcitabine + docetaxel + bevacizumab + sorafenib. 3B. Control, paclitaxel + carboplatin, ABI-007 + carboplatin. 3C. Control, paclitaxel + cisplatin, ABI-007 + cisplatin. 3D. Control, sorafenib + docetaxel + bevacizumab, sunitinib + docetaxel + bevacizumab, ABI-007 + bevacizumab.
[00014] Fig. 4 show the result of a chemotherapy sensitivity study in the non small cell lung cancer xenograft model using control, sorafenib + bevacizumab (AVASTIN), sorafenib + bevacizumab + irinotecan, etoposide + cisplatin + bevacizumab, sunitinib + bevacizumab, oxaliplatin + Alimta, and rapamune + TARCEVA.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[00015] In order to develop and establish transplantable models of disease for leiomyosarcoma
(LMS) and non-small cell lung cancer (NSCLC) and evaluate the potential benefit of chemotherapeutic agents, and in particular newly approved or experimental agents and novel combination therapies, or personalized treatments, in one embodiment samples of a patient's LMS or NSCLC tumor can be xenografted into immunodeficient mice to provide a means for identifying the optimal agent(s) for treatment. In another embodiment, a xenotransplant model of LMS or NSCLC can be established to provide a method for assessing various chemotherapeutic agents, or combinations thereof, dosing regiments and variations thereof, generally on these types of cancer.
[00016] In order to develop and establish transplantable models of disease for leiomyosarcoma
(LMS) and evaluate the potential of newly approved agents and novel combination therapies, LMS tumors were removed from patients and fragments xenografted into male CD-I nude mice. Tumors were propagated and amplified until growth was stable and the take rate was >80%; molecular profiling was then performed on each tumor to establish baseline levels of relevant proteins and signaling molecules. Following establishment, these models were evaluated for sensitivity towards a panel of single agent and combination therapies, to identify parameters of inhibition: tumor growth inhibition (TGI) and the tumor growth delay (TGD). As will be shown in the examples below, treatment with bevacizumab potentiated the efficacy of other tested regimens. Impressive growth inhibition was found with ABI-007 in P-9857-PC
combination with bevacizumab. As some treatments resulted in selective activity for LMS tumors, such as docetaxel not potentiating effects, shows specificity of the model.
[00017] A similar procedure was followed to establish a xenograft model of NSCLC and perform chemotherapeutic agent testing thereon.
[00018] The nude mouse LMS and NSCLC models permit evaluation of single or combination therapies using approved or experimental therapeutic agents. Non-limiting examples of such agents include the following agents. Docetaxel (TAXOTERE) is a member of the taxane class of chemotherapy drugs, and is a semi-synthetic analogue of paclitaxel (Taxol®), an extract from the rare Pacific yew tree Taxus brevifolia. Sorafenib (NEXAVAR) is a small molecular inhibitor of Raf kinase, PDGF (platelet- derived growth factor) and VEGF receptor kinase. Sunitinib (SUTENT) is a small molecule receptor tyrosine kinase inhibitor. ABI-007 belongs to the family of drugs called mitotic inhibitors. It is also called nanoparticle paclitaxel, protein-bound paclitaxel, paclitaxel (Albumin-Stabilized Nanoparticle Formulation), and Abraxane. Paclitaxel (TAXOL) is an anti-cancer taxane drug isolated the compound from the bark of the Pacific yew tree, Taxus brevifolia. Bevacizumab (AVASTIN) is a monoclonal antibody that works by attaching to and inhibiting the action of vascular endothelial growth factor (VEGF) in laboratory experiments. Pemetrexed (ALIMTA) is a new drug used for malignant pleural mesothelioma, and non-small cell lung cancer. Sirolimus (RAPAMUNE) is an immunosuppressive agent, and erlotinib (TARCEVA) is a Tarceva is a small molecule human epidermal growth factor type 1/epidermal growth factor receptor (HER1/EGFR) inhibitor. Bortezomib (VELCADE), gemcitabine (GEMZAR), irinotecan (CAMPTO), ifosfamide (MITOXANA), and fludarabine (FLUDARA) are other examples of chemotherapeutic agents used singly or in combination in cancer therapy.
[00019] As will be seen in the examples below, treatment with some combination therapies was sufficient to produce extended tumor growth inhibition. In LMS, treatment with bevacizumab potentiated the effect of most tested regimens while docetaxel did not provide a benefit in these studies. Comparable TGI effects were noted with sorafenib or sunitinib combination therapies. Moreover, impressive tumor growth inhibition and partial/complete responses were reported with ABI-007 in combination with bevacizumab; paclitaxel was ineffective towards this model. P-9857-PC
[00020] In NSCLC, the combination of sorafenib and bevacizumab (Avastin), or sorafenib, bevacizumab and irinotecan, or etoposide, cisplatin and bevacizumab showed significant inhibition of tumor growth.
[00021] Growth of these models was stable and consistent through several studies. In addition, activity of some single agents and combinations was model-specific and correlated well with donor patient's clinical responses. Thus these models should be further pursued as promising tools for diagnostic and therapeutic discovery and development
EXAMPLES
[00022] Tumor Models. LMS 01 is a leiomyosarcoma originating from a 55 year old Caucasian female. Male CD-I nude mice were implanted subcutaneously by trocar with fragments of the LMS human tumor harvested from tumors growing in nude mice hosts. When tumors reached approximately 100 mm3, animals were pair-matched by tumor volume into treatment and control groups and dosing initiated (Day 1). Mice were weighed and tumor measurements taken twice weekly by Vernier caliper. Tumor volume was calculated by conversion of two-dimensional caliper measurements using the equation: a. [Tumor Volume (mm3) = Width2 (mm) x Length (mm) x 0.52]
[00023] At study completion, mean tumor growth inhibition of each treated group was compared with vehicle control and a TGI value calculated using the formula: a. [l-(Final Tx. Volume)-(Initial Tx. Volume) / (Final CtI. Volume)-(Initial CtI Volume) x 100%]
[00024] Individual mice possessing tumors measuring less than on Day 1 were classified as having partial response (PR) and a percent tumor regression (%TR) value was determined using the formula : a. [1 -(Final Tumor Volume / Initial Tumor Volume) x 100%]
[00025] If partial tumor responses were reported in multiple animals within one group, a mean PR value was determined. Individual mice lacking palpable tumors were classified as undergoing complete response (CR).
[00026] Statistical Analysis. Final tumor volumes were compared using a two-tailed ANOVA followed by the Neumann Keul's multiple comparisons test. P-9857-PC
Example 1
Chemotherapeutic Agent Testing
[00027] The table below sets forth the mouse treatment regimens for the experiments in this group, as well as the final tumor volume and calculations thereof.
LMS STUDY #1
FINAL TUMOR VOLUME DATA (DAY 78)
DOSE
GROUP ROUTE; SCHEDULE MEAN (MM3) ± SEM MG/KG %TGI #PR/CR %TR
No Treatment — 2175 ± 753 lrinotecan /Bevacizumab 100/10 IP;Q7Dx3x2/IP;Q3Dx10x2 1529 ± — 33 0/2
Bortezomib/Bevacizumab 1/10 IV;Q3Dx6x2/IP;Q3Dx10x2 413 ± 252 83 0/0
Sirolimus/Bevacizumab 8/10 PO;QDx14x2/IP;Q3Dx10x2 223 ± 153 92 1/0 25
Gemcitabine 40 IP;Q3Dx4x2
48 ± 32 100 0/0 Docetaxel/ Bevacizumab 6.3/10 IV;Q2Dx3x2/IP;Q3Dx10x2
Temozolomide 70 IP;QDx5x2 2865 ± 336 — 1/0 87
Temozolomide/ Sorafenib 70/60 IP;QDx5x2/PO;QDx10x2 463 ± — 81 0/2
N-3-7 on Day 1
[00028] Fig. 1 A-B show the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: IA. Combination of irinotecan + bevacizumab, bortezomib + bevacizumab, sirolimus + bevacizumab, and gemcitabine + bevacizumab. IB. Control, temozolomide, and temozolomide + sorafenib.
[00029] Treatment with bevacizumab potentiated the effects of the tested regimens. Temozolomide alone was not effective.
Example 2
Chemotherapeutic Agent Testing
[00030] The table below sets forth the mouse treatment regimens for the experiments in this group, as well as the final tumor volume and calculations thereof. P-9857-PC
LMS STUDY #2
FINAL TUMOR VOLUME DATA (DAY 98>
DOSE
GROUP ROUTE; SCHEDULE MEAN (MM3) ± SEM MG/KG %TGI #PR/CR %TR
No Treatment 2620 ± 1337
Sunitlnib 40 PO;QDx21 162S ± 781 39 0/0 —
Sunitinib/ Docetaxel 40/6.3 PO;QDx21/IV;Q2Dx3 1598 ± 969 40 0/0 —
Sunitlnib/ Bevacizumab 40/10 PO; QDX21/ Q3Dx10 497 ± 125 84 1/0 20
Sunitinib 40 PO; QDx21 520 ± 228 81 0/0 — Docetaxel/Bevacizumab 6.3/10 IV;Q2Dx3/IP;Q3Dx10
Sorafenib 60 PO;QDx9 694 ± 71 76 1/0 29 Docetaxel/ Bevacizumab 6.3/10 IV;Q2Dx3/IP;Q3Dx10
[00031 ] Fig. 2 shows the result of a chemotherapy sensitivity study in the human leiomyosarcoma xenograft model using the following agent or combination of agents: control, sunitinib, sunitinib + docetaxel, sunitinib + docetaxel + bevacizumab, sunitinib + bevacizumab. The data show that combination with docetaxel did not provide a benefit.
Example 3
[00032] The table below sets forth the mouse treatment regimens for the experiments in this group, as well as the final tumor volume and calculations thereof.
P-9857-PC
LMS STUDY #3
FINAL TUMOR VOLUME DATA (DAY 92)
DOSE
GROUP ROUTE; SCHEDULE MEAN (MM3) ± SEM %TGI #PR/CR %TR MG/KG
No Treatment — — 2106 ± 677 — — —
Sorafenib 60 PO;QDx10 760 ± 215 69 0/0 — Docetaxel/ Bevacizumab 6.5/10 IV;Q2D3/IP;Q3Dx10
Sunitinib 40 PO;QDx10 883 ± 200 63 1/0 79 Docetaxel/ Bevacizumab 6.5/10 IV;O2Dx3/IP;Q3Dx10
Paclitaxel/ Carboplatin 6/50 IP;QDx5/IP;QDx1 3552 ± 1132 — 1/0 14
Paclitaxel/ Cisplatin 6/2 IP;QDx5/IP;QDx5 3910 ± 965 — 0/0 —
ABI-007/Bevacizumab 50/10 IV;Q4Dx3/IP;Q3Dx10 463 ± .._ 89 4/1 63
ABI-007/ Carboplatin 50/50 IV;Q4Dx3/IP;QDx1 989 ± 339 57 0/0 —
ABI-007/ Cisplatin 50/2 IV;Q4Dx3/IP;QDx5 1720 ± 516 20 0/0 —
Gemcitabine 40 IP;Q3Dx4 200 ± 56 97 0/0 — Docetaxel/ Bevacizumab 6.5/10 IV;Q2Dx3/IP;Q3Dx10
Gemcitabine/ Docetaxel 40/6.5 IP;Q3Dx4 675 ± 280 75 1/1 88 Bevacizumab/ lrinotecan 10/50 IP;Q3Dx10/IP;QDx3
Gemcitabine/ Docetaxel 40/6.5 IP; Q3Dx4/IV;Q2Dx3 91 ± __ 98 0/0 — Bevacizumab/ Temozolomide 10/70 IP;Q3Dx10/IP;QDx5
Gemcitabine/ Docetaxel 40/6.5 IP;Q3Dx4/IV;Q2Dx3 448 ± 209 84 0/0 — Bevacizumab/ Sorafenib 10/60 IP;Q3Dx10/lP;QDx10
N.5-9 on Day 1
[00033] The data collected over time is shown in Figs. 3 A-D. Treatment with some combination therapies was sufficient to produce extended tumor growth inhibition in each study. Treatment with bevacizumab potentiated the effect of most tested regimens while docetaxel did not provide a benefit in these studies. Comparable TGI effects were noted with sorafenib or sunitinib combination therapies. Impressive tumor growth inhibition and partial/complete responses were reported with ABI-007 in combination with bevacizumab; paclitaxel was ineffective towards this model
Example 4 Xenograft model of Non-small cell lung cancer
[00034] Tumor tissue fragments from a non-small cell lung cancer from a 50 year old male were implanted subcutaneously into male CD-I nude mice by trocar. When tumors reached approximately 100 mm3, animals were pair-matched by tumor volume into treatment and control groups and dosing initiated (Day 1). Mice were weighed and tumor measurements taken twice weekly by Vernier caliper. P-9857-PC
Tumor volume was calculated by conversion of two-dimensional caliper measurements using the equation: a. [Tumor Volume (mm3) = Width2 (mm) x Length (mm) x 0.52]
[00035] At study completion, mean tumor growth inhibition of each treated group was compared with vehicle control and a TGI value calculated using the formula: a. [1 -(Final Tx. Volume)-(Initial Tx. Volume) / (Final CtI. Volume)-(Initial CtI Volume) x 100%]
[00036] Individual mice possessing tumors measuring less than on Day 1 were classified as having partial response (PR) and a percent tumor regression (%TR) value was determined using the formula : a. [ 1 -(Final Tumor Volume / Initial Tumor Volume) x 100%]
[00037] If partial tumor responses were reported in multiple animals within one group, a mean PR value was determined. Individual mice lacking palpable tumors were classified as undergoing complete response (CR).
[00038] Statistical Analysis. Final tumor volumes were compared using a two-tailed ANOVA followed by the Neumann Keul's multiple comparisons test.
[00039] Fig. 4 shows the result of a chemotherapy sensitivity study in the non small cell lung cancer xenograft model using control, sorafenib + bevacizumab (Avastin), sorafenib + bevacizumab + irinotecan, etoposide + carboplatin + bevacizumab, sunitinib + bevacizumab, oxaliplatin + Alimta, and rapamune + Tarceva. The combination of sorafenib and bevacizumab (Avastin), or sorafenib, bevacizumab and irinotecan, or etoposide, cisplatin and bevacizumab showed significant inhibition of tumor growth.
[00040] Growth of these models was stable and consistent through several studies. In addition, activity of some single agents and combinations was model-specific and correlated well with donor patient's clinical responses.
[00041] While certain features have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

P-9857-PCCLAIMSWhat is claimed is:
1. A human leiomyosarcoma xenograft model capable of stable propagation in immunodeficient mice.
2. The model of claim 1 having sensitivity of tumor growth to single or combinations of chemotherapeutic agents administered to the mouse
3. The model of claim 1 wherein treatment with sorafenib or sunitinib show significant tumor growth inhibition.
4. The model of claim 3 wherein bevacizumab in combination therewith enhances tumor growth inhibition.
5. The model of claim 1 wherein the immunodeficient mice are nude mice.
6. The model of claim 1 wherein treatment with AB 1-007 in combination with bevacizumab provided complete responses.
7. The model of claim 1 wherein paclitaxel is ineffective.
8. The model of claim 1 wherein the xenograft is subcutaneous.
9. A method for identifying an optimal chemotherapeutic regimen for a human leiomyosarcoma tumor in a patient by the steps of
(1 ) establishing a xenograft of the tumor in immunodeficient mice,
(2) confirming the phenotypic stability of the tumor, and
(3) evaluating the effect on tumor growth inhibition by at least one chemotherapeutic regimen, such as by a single agent or at least one combination of chemotherapeutic agents, P-9857-PC
wherein an effective chemotherapeutic regimen in the xenograft model identifies a regimen useful for treatment of the disease in the patient.
10. The method of claim 9 wherein an optimal schedule and dose of chemotherapeutic agent administration is determined then applied to the patient.
11. The method of claim 9 wherein the immunodeficient mice are nude mice.
12. A method for assessing the effect of a composition or treatment on human leiomyosarcoma, comprising the steps of a) providing an immunodeficient mouse comprising a xenograft of human leiomyosarcoma, wherein the xenograft is allowed to grow for a sufficient time to permit the detection of a tumor, b) subjecting the mouse to the composition or treatment, and c) determining the effect of the composition or treatment on the growth of the xenograft in the mouse.
13. The method of claim 13 wherein the xenograft is subcutaneous.
14. The method of claim 12 wherein the immunodeficient mouse is a nude mouse.
15. An immunodeficient mouse having a xenograft of a human leiomyosarcoma.
16. The mouse of claim 15 wherein the xenograft is subcutaneous.
17. The mouse of claim 15 wherein the immunodeficient mouse is a nude mouse.
18. A human non-small cell lung cancer xenograft model capable of stable propagation in immunodeficient mice.
19. The model of claim 18 having sensitivity of tumor growth to single or combinations of chemotherapeutic agents administered to the mouse P-9857-PC
20. The model of claim 18 wherein treatment with a combination of sorafenib and bevacizumab (Avastin), or sorafenib, bevacizumab and irinotecan, or etoposide, cisplatin and bevacizumab show significant inhibition of tumor growth.
21. The model of claim 18 wherein the immunodeficient mice are nude mice.
22. The model of claim 18 wherein the xenograft is subcutaneous.
23. A method for identifying an optimal chemotherapeutic regimen for a human non-small cell lung cancer tumor in a patient by the steps of
(1) establishing a xenograft of the tumor in immunodeficient mice,
(2) confirming the phenotypic stability of the tumor, and
(3) evaluating the effect on tumor growth inhibition by at least one chemotherapeutic regimen, such as by a single agent or at least one combination of chemotherapeutic agents, wherein an effective chemotherapeutic regimen in the xenograft model identifies a regimen useful for treatment of the disease in the patient.
24. The method of claim 23 wherein an optimal schedule and dose of chemotherapeutic agent administration is determined then applied to the patient.
25. The method of claim 23 wherein the immunodeficient mice are nude mice.
26. A method for assessing the effect of a composition or treatment on human 1 human non-small cell lung cancer, comprising the steps of a) providing an immunodeficient mouse comprising a xenograft of human non-small cell lung cancer, wherein the xenograft is allowed to grow for a sufficient time to permit the detection of a tumor, b) subjecting the mouse to the composition or treatment, and c) determining the effect of the composition or treatment on the growth of the xenograft in the mouse.
27. The method of claim 26 wherein the xenograft is subcutaneous. P-9857-PC
28. The method of claim 26 wherein the immunodeficient mouse is a nude mouse.
29. An immunodeficient mouse having a xenograft of a human non-small cell lung cancer.
30. The mouse of claim 29 wherein the xenograft is subcutaneous.
31. The mouse of claim 29 wherein the immunodeficient mouse is a nude mouse.
PCT/US2008/005936 2007-05-11 2008-05-09 Human leiosarcoma and non small cell lung cancer lung xenograft models WO2008140751A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040037815A1 (en) * 2000-08-03 2004-02-26 Clarke Michael F. Isolation and use of solid tumor stem cells
US20060233810A1 (en) * 2005-04-15 2006-10-19 Yaolin Wang Methods and compositions for treating or preventing cancer
US20060263434A1 (en) * 2005-02-18 2006-11-23 Desai Neil P Combinations and modes of administration of therapeutic agents and combination therapy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040037815A1 (en) * 2000-08-03 2004-02-26 Clarke Michael F. Isolation and use of solid tumor stem cells
US20060263434A1 (en) * 2005-02-18 2006-11-23 Desai Neil P Combinations and modes of administration of therapeutic agents and combination therapy
US20060233810A1 (en) * 2005-04-15 2006-10-19 Yaolin Wang Methods and compositions for treating or preventing cancer

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