LIPOSOME AND POLYCATIONIC GENE THERAPY FOR OSTEOSARCOMA
Eugenie S Kleinerman, Professor
University Of Texas Md Anderson Can Ctr, Unit 0176, Houston, Tx 77030-4009
Grant 5R01CA042992-24 from National Cancer Institute
Keywords: 0-11 years old; 21+ years old; 9-NC; 9-nitrocamptothecin; Adjuvant Chemotherapy; Adolescent; Adolescent Youth; Adult; Adverse effects; Aerosol Drug Therapy; Aerosols; Antimorphic mutation; Athymic Nude Mouse; Bone Sarcoma; Cell Communication and Signaling; Cell Growth in Number; Cell Line; Cell Lines, Strains; Cell Multiplication; Cell Proliferation; Cell Signaling; CellLine; Cells; Cellular Proliferation; Chemotherapy Protocol; Chemotherapy Regimen; Chemotherapy, Adjuvant; Chemotherapy, Cancer, General; Chemotherapy-Oncologic Procedure; Child; Child Youth; Childhood; Children (0-21); Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Combination Chemotherapy Regimen; Coughing; Data; Death Domain; Dominant Negative; Dominant-Negative Mutant; Dominant-Negative Mutation; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drug Therapy, Adjuvant; Drug Therapy, Aerosol; Early-Stage Clinical Trials; Edodekin Alfa; Encapsulated; Fatigue; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genetic Intervention; Grant; Host resistance; Human; Human, Adult; Human, Child; Human, General; IL-12; IL-12 gene; IL12; In Vitro; Interleukin-12; Interleukin-12 Gene; Intervention, Genetic; Intracellular Communication and Signaling; Investigation; Knockout Mice; Laboratories; Lack of Energy; Liposomal; Liposomes; Lung; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediator; Mediator of Activation; Mediator of activation protein; Metastasis; Metastasis to the Lung; Metastasize; Metastatic Neoplasm; Metastatic Neoplasm to the Lung; Metastatic Osteogenic Sarcoma; Metastatic Osteosarcoma; Metastatic Tumor; Metastatic Tumor to the Lung; Metastatic to; Methods; Mice; Mice, Athymic; Mice, Knock-out; Mice, Knockout; Mice, Nude; Microscopic; Modeling; Molecular Biology, Gene Therapy; Murine; Mus; NKSF; Natural Killer Cell Stimulatory Factor; Neoplasm Metastasis; New Agents; Nitro camptothicin; Nitrocamptothecin; Nude Mice; Null Mouse; Organ; Osseous Sarcoma; Pathway interactions; Patients; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Play; Pre-Clinical Model; Preclinical Models; Quimioterapia; Relapse; Respiratory System, Lung; Role; Sarcoma, Osteogenic; Secondary Neoplasm; Secondary Tumor; Signal Transduction; Signal Transduction Pathway; Signal Transduction Systems; Signaling; Site; Skeletal Sarcoma; Sore Throat; Stream; System; System, LOINC Axis 4; Therapeutic; Therapy, DNA; Toxic effect; Toxicities; Treatment Efficacy; Treatment Side Effects; Tumor Cell; Tumor Cell Migration; Up-Regulation; Up-Regulation (Physiology); Upregulation; Wheezing; Wheezings; adult human (21+); adult youth; aerosol therapy; base; biological signal transduction; cancer chemotherapy; cancer metastasis; chemotherapy; children; clinical investigation; cultured cell line; gene therapy; genetic therapy; in vivo; juvenile; juvenile human; metastatic process; migration; mouse model; neoplastic cell; new approaches; novel; novel approaches; novel strategies; novel strategy; osteochondrosarcoma; osteoid sarcoma; osteosarcoma; overexpression; pathway; pediatric; phase 1 study; phase 1 trial; phase I trial; protocol, phase I; pulmonary; pulmonary metastasis; response; side effect; social role; therapeutic efficacy; therapeutically effective; therapy adverse effect; treatment adverse effect; tumor; vector; wheeze; young adult; youngster
Project start date: 1986-08-01
Project end date: 2010-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
5R01CA042992-24 (2010): $263918
Sponsored Links Excellgen http://Excellgen.com
LIPOSOME THERAPY--A POTENTIAL ADJUVANT FOR CHILDHOOD
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 5R01CA042992-04 from National Cancer Institute IRG: ET
Abstract: The major objective to evaluate the function of blood monocytes from children with osteosarcoma and determine their ability to be activated by liposome-encapsulated immunomodulators to lyse tumor cells. In addition, we intend to monitor this monocyte function in each individual patient from the time of diagnosis, through chemotherapy and surgery and after all treatment. This project is based on the recent observation that normal human blood monocytes can be activated by liposome-encapsulated immunomodulators to selectively lyse malignant cells in vitro. Normal cells are not lysed under similar conditions or even when co-cultivated together with tumor cells. Furthermore, multiple intravenous injection of liposome-encapsulated activators into mice with well established spontaneous lung metastases have resulted in both the activation of pulmonary macrophages and the eradication of pulmonary metastases. Osteosarcoma appears an ideal disease in which to employ liposome-encapsulated immunomodulators since its natural history parallels that of the animal model used in these in vivo liposome studies. Despite removal of the primary bone tumor and the administration of adjuvant chemotherapy, approximately 40% of children with this disease develop pulmonary metastases. Our goal is to employ activated macrophages as an adjuvant therapy to eliminate residual tumor cells in the lung and we believe that patients with osteosarcoma may benefit from the inclusion of liposome-encapsulated immunomodulators as part of their therapy. However, prior to the initiation of any such therapy, it is imperative that the monocyte function of patients with osteosarcoma be evaluated, including the effects of chemotherapy, surgery and the tumor burden. Only then can we determine if all patients are candidates for such biological therapy and when is the ideal time to commence such adjuvant therapy. For example, if chemotherapy transiently depresses monocyte function, it will be important to know the time frame of the recovery phase before proposing in vivo treatment schedules with liposome-encapsulated monocyte activators. It is expected that these experiments will lay the groundwork for designing a protocol that includes liposome-encapsulated monocyte activators as a part of the adjuvant chemotherapy treatment not only for osteosarcoma, but possible for other malignancies as well.
Keywords: BIOLOGICAL TRANSPORT, MEMBRANE MODELS, LIPOSOMES, NEOPLASMS, PEDIATRIC, NEOPLASMS, SARCOMA, NEOPLASTIC THERAPY, CANCER CHEMOTHERAPY, BLOOD AND RE SYSTEM, MACROPHAGES, BLOOD CELLS, MONOCYTES, GENETICS, GENES, GENE EXPRESSION, IMMUNOLOGY, IMMUNOMODULATING AGENTS, NEOPLASMS GENETICS, NEOPLASMS IMMUNIZATION (IMMUNOTHERAPY), NEOPLASMS OF RESPIRATORY SYSTEM, LUNG NEOPLASMS, NEOPLASTIC GROWTH, NEOPLASMS METASTASIS, immunogenetics
Project start date: 1986-08-01
Project end date: 1990-05-31
LIPOSOME THERAPY--A POTENTIAL ADJUVANT FOR OSTEOSARCOMA
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 5R01CA042992-07 from National Cancer Institute IRG: ET
Abstract: The major objective of this proposal is to determine the efficacy of liposomal MTP ([L-MTP-PE] a monocyte/macrophage activator) in controlling or preventing lung metastases in patients with osteosarcoma who have relapsed on chemotherapy. The majority of children who present with osteosarcoma have undetectable pulmonary micrometastases. Despite surgical resection of the primary tumor plus adjuvant chemotherapy the metastases free survival (MFS) at 2 yrs is 66%. The majority of patients who develop pulmonary metastases do so while receiving chemotherapy. These patients have a poor prognosis. Although they can be rendered "disease free" by surgery, the recurrence rate is 60-70% within 1 year. Salvage chemotherapy has had little effect on the MFS of these individuals. Our proposal is to employ L-MTP-PE therapy in a phase II trial in this group of patients. The goal is to activate the body s monocytes and pulmonary macrophages to eradicate the residual micrometastases that we know exist in the lungs. The activation of monocyte tumoricidal properties was demonstrated in 20 of 28 patients receiving i.v. L-MTP-PE in a phase I trial. This activity correlated with IL-1 secretion. Following the surgical removal of visible pulmonary metastases, patients will receive L-MTP-PE twice a wk. for 3 mo. (no other therapy). Relapse rates will be compared to historical controls. Serum IL-1, TNF and IL-6 levels will be monitored as well as monocyte tumoricidal activity, monocyte membrane IL-1 and TNF, and monocyte IL-1 and TNF secretion, pre, during and post L-MTP-PE. In addition normal monocytes will be incubated with L-MTP-PE. The secretion and mRNA expression of IL-1, TNF and IL-6 will be monitored over time to determine which cytokine(s) is induced first and which, if any, are stimulated secondarily. These laboratory studies will help to elucidate the mechanism of action of L-MTP-PE. The proposed clinical and laboratory studies together should lay the ground work for future adjuvant trials using L-MTP-PE in the treatment of osteosarcoma and other malignancies.
Keywords: human therapy evaluation, liposome, neoplasm /cancer chemotherapy, osteogenic sarcoma, pediatric neoplasm /cancer, clinical study /trial, immunomodulator, interleukin 1, interleukin 6, lung neoplasm, macrophage, metastasis, monocyte, neoplasm /cancer immunotherapy, tumor necrosis factor alpha, computed axial tomography, enzyme linked immunosorbent assay, human clinical subject
Project start date: 1986-08-01
Project end date: 1993-05-31
5R01CA042992-07 (1992): $138543
5R01CA042992-10 (1995): $171393
5R01CA042992-09 (1994): $161504
Liposome And Polycationic Gene Therapy For Osteosarcoma
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 5R01CA042992-21 from National Cancer Institute IRG: DT
Abstract: Despite multiple changes in adjuvant chemotherapy, the 2-year metastasis-free survival in osteosarcoma (OS) has remained stagnant at 65-70% for the past 10 years. The lung is the most common and often the only site of metastases. Our laboratory has focused on understanding the mechanisms involved in OS metastasis to the lung and in identifying novel ways to treat OS pulmonary metastases. Using our experimental human OS lung metastasis nude mouse model we demonstrated that Fas expression correlates inversely with metastatic potential. We hypothesized that because FasL is constitutively expressed in the lung, that OS cells expressing high levels of Fas will be eliminated upon migration into the lung, whereas those with low or no Fas expression will evade this form of host resistance. We also demonstrated that IL-12 upregulated tumor Fas expression in vitro, altered metastatic potential and that the IL-12 gene could be delivered by aerosol using polyethyleneimine (PEI) as a vector delivery system. Aerosol PEIIL-12 upregulated tumor Fas in vivo and induced regression of established microscopic pulmonary metastases. We also demonstrated that aerosol delivery of liposome-encapsulated 9-nitrocamptothecin (L-9NC) upregulated tumor Fas expression and resulted in eradication of OS lung metastases. A phase I trial in adults using aerosol L-9NC demonstrated the feasibility of aerosol chemotherapy. No children or adolescents were treated in this phase I trial. We now propose to (1) perform a phase I/II clinical trial with aerosol L-9NC in patients 10-25 years old with metastases in the lung; (2) determine whether inhibiting Fas signalling impacts tumor cell clearance, cell proliferation and the metastatic potential of OS cells to the lung; (3) determine whether the Fas pathway is critical for both aerosol IL-12 and L-9NC activity in vivo. Together these investigations should give an indication of the importance of the Fas pathway in the metastatic process of OS and in the therapeutic efficacy of both aerosol L-9NC and PEIIL-12 gene therapy. The long term objectives are to develop aerosol therapy for metastatic OS and other tumors that relapse in the lung.
Keywords: aerosol, gene therapy, liposome, lung, osteosarcoma, apoptosis, athymic mouse, base, birth, cell, cell line, cell proliferation, chemotherapy, children, clinical trial, clinical trial phase I, death, fatigue, gene, human, inhalation drug administration, metastasis, model, neoplasm /cancer, organ, pharyngitis, play, respiratory reflex, role, therapy, clinical research
Project start date: 1986-08-01
Project end date: 2010-12-31
5R01CA042992-21 (2007): $263918
5R01CA042992-19 (2004): $339750
5R01CA042992-18 (2003): $339750
Sponsored Links Excellgen http://Excellgen.com
5R01CA042992-17 (2002): $339750
5R01CA042992-16 (2001): $339750
LIPOSOME THERAPY--A POTENTIAL ADJUVANT FOR OSTEOSARCOMA
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 5R01CA042992-14 from National Cancer Institute IRG: ET
Abstract: Applicant s ) The major objective of this application is to determine whether chemotherapy + liposome-encapsulated MTP-PE (L-MTP- PE), a monocyte/ macrophage activator, improves the metastasis-free survival of newly diagnosed OS patients. A randomized phase III trial will be performed in conjunction with POG and CCSG co- operative groups. will evaluate the immunomodulatory activity of L-MTP-PE + chemotherapy to determine if certain chemotherapy regimens alter in vivo immune response to L-MTP-PE. The development of pulmonary metastases is a major problem in OS. The 2-yr metastasis-free survival is 65 percent regardless of the chemotherapy regimen employed. More than 50 percent of relapses occur during year 1 while the patients are receiving chemotherapy. No improvements have been made in the past 10 yrs. In a phase II trial with relapsed OS, has demonstrated the in vivo immunostimulating activity of L-MTP-PE. Circulating TNF, IL-6, IL-8, CRP and neopterin were induced by L-MTP-PE. Unique histologic changes in pulmonary lesions resected after L-MTP-PE therapy were demonstrated and the progression-free interval was significantly increased following 24 wks of L-MTP-PE treatment. A phase IIb trial showed that L-MTP- PE can safely be administered with ifosfamide (IFX) with no increase in IFX toxicity or decrease in immune stimulation. This application is to determine the efficacy of L-MTP-PE + combination chemotherapy in newly diagnosed OS. s goal is to activate the body s monocytes and pulmonary macrophages to eradicate the residual tumor cells not killed by the chemotherapy. Patients will be randomized to 2 different chemotherapy regimens. A second randomization determines if L-MTP-PE is added to the treatment. This 4-arm study investigates the impact of using L-MTP-PE with different chemotherapy combinations. Patients receive chemotherapy for 10 wks prior to tumor resection then chemotherapy plus or minus L-MTP-PE post operatively. Plasma cytokine levels and monocyte tumoricidal activity will be quantified before and at various times after administration of L-MTP-PE + chemotherapy to determine if certain chemotherapy combinations impair response to L-MTP-PE. has shown that when patients receive ADR + CTX together, their monocytes were unresponsive to L-MTP-PE in vitro. Therefore, the immunostimulating capacity of L-MTP-PE may be diminished by certain drug combinations which may in turn impact on its effectiveness and ultimately on the success rate of one arm of the trial. Predicting patient outcomes by monitoring monocyte tumoricidal activity is another goal since increased monocyte tumoricidal activity during wk 1 of L-MTP-PE therapy correlated with the clinical response of stage III and IV melanoma patients. Finally, a nude mouse OS model will determine the activity of oral L-MTP-PE. L-MTP-PE is presently given i.v. twice weekly for 36 wks. The ability to give L-MTP-PE orally would greatly reduce the cost and inconvenience of this therapy.
Keywords: combination antineoplastic therapy, human therapy evaluation, ifosfamide, liposome, macrophage activating factor, neoplasm /cancer chemotherapy, osteosarcoma, alveolar macrophage, cis platinum compound, clinical trial phase II /III /IV, cytokine, cytotoxicity, disease model, doxorubicin, immunomodulator, leukocyte activation /transformation, melanoma, methotrexate, monocyte, neoplasm /cancer remission /regression, neoplastic cell, athymic mouse, clinical research, human subject, oral administration
Project start date: 1986-08-01
Project end date: 2000-03-31
5R01CA042992-14 (1999): $226225
5R01CA042992-13 (1998): $200497
5R01CA042992-12 (1997): $169325
Liposome And Polycationic Gene Therapy For Osteosarcoma
Eugenie S Kleinerman, Professor And Head
Pediatricsuniversity Of Texas Md Anderson Can Ctr
Grant 5R01CA042992-23 from National Cancer Institute IRG: DT
Project start date: 1986-08-01
Project end date: 2010-12-31
Grants awarded to Eugenie S Kleinerman
LIPOSOME THERAPY--A POTENTIAL ADJUVANT FOR CHILDHOOD
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 1R01CA042992-01 from National Cancer Institute IRG: ET
Abstract: The major objective to evaluate the function of blood monocytes from children with osteosarcoma and determine their ability to be activated by liposome-encapsulated immunomodulators to lyse tumor cells. In addition, we intend to monitor this monocyte function in each individual patient from the time of diagnosis, through chemotherapy and surgery and after all treatment. This project is based on the recent observation that normal human blood monocytes can be activated by liposome-encapsulated immunomodulators to selectively lyse malignant cells in vitro. Normal cells are not lysed under similar conditions or even when co-cultivated together with tumor cells. Furthermore, multiple intravenous injection of liposome-encapsulated activators into mice with well established spontaneous lung metastases have resulted in both the activation of pulmonary macrophages and the eradication of pulmonary metastases. Osteosarcoma appears an ideal disease in which to employ liposome-encapsulated immunomodulators since its natural history parallels that of the animal model used in these in vivo liposome studies. Despite removal of the primary bone tumor and the administration of adjuvant chemotherapy, approximately 40% of children with this disease develop pulmonary metastases. Our goal is to employ activated macrophages as an adjuvant therapy to eliminate residual tumor cells in the lung and we believe that patients with osteosarcoma may benefit from the inclusion of liposome-encapsulated immunomodulators as part of their therapy. However, prior to the initiation of any such therapy, it is imperative that the monocyte function of patients with osteosarcoma be evaluated, including the effects of chemotherapy, surgery and the tumor burden. Only then can we determine if all patients are candidates for such biological therapy and when is the ideal time to commence such adjuvant therapy. For example, if chemotherapy transiently depresses monocyte function, it will be important to know the time frame of the recovery phase before proposing in vivo treatment schedules with liposome-encapsulated monocyte activators. It is expected that these experiments will lay the groundwork for designing a protocol that includes liposome-encapsulated monocyte activators as a part of the adjuvant chemotherapy treatment not only for osteosarcoma, but possible for other malignancies as well.
Keywords: BIOLOGICAL TRANSPORT, MEMBRANE MODELS, LIPOSOMES, EXPERIMENTAL THERAPEUTICS STUDY SECTION, NEOPLASMS, PEDIATRIC, NEOPLASMS, SARCOMA, NEOPLASTIC THERAPY, CANCER CHEMOTHERAPY, BLOOD AND RE SYSTEM, MACROPHAGES, BLOOD CELLS, MONOCYTES, GENETICS, GENES, GENE EXPRESSION, IMMUNOGENETICS (GENERAL), IMMUNOLOGY, IMMUNOMODULATING AGENTS, NEOPLASMS GENETICS, NEOPLASMS IMMUNIZATION (IMMUNOTHERAPY), NEOPLASMS OF RESPIRATORY SYSTEM, LUNG NEOPLASMS, NEOPLASTIC GROWTH, NEOPLASMS METASTASIS
Project start date: 1986-08-01
Project end date: 1990-05-31
LIPOSOME THERAPY--A POTENTIAL ADJUVANT FOR OSTEOSARCOMA
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 2R01CA042992-05 from National Cancer Institute IRG: ET
Abstract: The major objective of this proposal is to determine the efficacy of liposomal MTP ([L-MTP-PE] a monocyte/macrophage activator) in controlling or preventing lung metastases in patients with osteosarcoma who have relapsed on chemotherapy. The majority of children who present with osteosarcoma have undetectable pulmonary micrometastases. Despite surgical resection of the primary tumor plus adjuvant chemotherapy the metastases free survival (MFS) at 2 yrs is 66%. The majority of patients who develop pulmonary metastases do so while receiving chemotherapy. These patients have a poor prognosis. Although they can be rendered "disease free" by surgery, the recurrence rate is 60-70% within 1 year. Salvage chemotherapy has had little effect on the MFS of these individuals. Our proposal is to employ L-MTP-PE therapy in a phase II trial in this group of patients. The goal is to activate the body s monocytes and pulmonary macrophages to eradicate the residual micrometastases that we know exist in the lungs. The activation of monocyte tumoricidal properties was demonstrated in 20 of 28 patients receiving i.v. L-MTP-PE in a phase I trial. This activity correlated with IL-1 secretion. Following the surgical removal of visible pulmonary metastases, patients will receive L-MTP-PE twice a wk. for 3 mo. (no other therapy). Relapse rates will be compared to historical controls. Serum IL-1, TNF and IL-6 levels will be monitored as well as monocyte tumoricidal activity, monocyte membrane IL-1 and TNF, and monocyte IL-1 and TNF secretion, pre, during and post L-MTP-PE. In addition normal monocytes will be incubated with L-MTP-PE. The secretion and mRNA expression of IL-1, TNF and IL-6 will be monitored over time to determine which cytokine(s) is induced first and which, if any, are stimulated secondarily. These laboratory studies will help to elucidate the mechanism of action of L-MTP-PE. The proposed clinical and laboratory studies together should lay the ground work for future adjuvant trials using L-MTP-PE in the treatment of osteosarcoma and other malignancies.
Keywords: BIOLOGICAL TRANSPORT, MEMBRANE MODELS, LIPOSOMES, NEOPLASMS OF SKELETAL SYSTEM, OSTEOGENIC SARCOMA, NEOPLASMS, PEDIATRIC, NEOPLASTIC THERAPY, CANCER CHEMOTHERAPY, THERAPY EVALUATION, HUMAN, BLOOD AND RE SYSTEM, MACROPHAGES, BLOOD CELLS, MONOCYTES, IMMUNITY, CYTOKINES, INTERLEUKIN 1, IMMUNITY, CYTOKINES, INTERLEUKIN 6, IMMUNITY, CYTOKINES, MONOKINES, TUMOR NECROSIS FACTOR, IMMUNOLOGY, IMMUNOMODULATING AGENTS, NEOPLASMS IMMUNIZATION (IMMUNOTHERAPY), NEOPLASMS OF RESPIRATORY SYSTEM, LUNG NEOPLASMS, NEOPLASTIC GROWTH, NEOPLASMS METASTASIS, HUMAN, CLINICAL, IMMUNOLOGICAL TESTS AND IMMUNOASSAY, ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RADIOGRAPHY, SCANNING, CAT
Project start date: 1986-08-01
Project end date: 1993-05-31
2R01CA042992-08 (1993): $158461
VACDXR W/ OR W/OUT IMMTHER FOR NEWLY DIAGNOSED HIGH RISK EWINGS SARCOMA
Eugenie S Kleinerman, Professor And Head
University Of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225
Grant 5M01RR002558-150202 from National Center For Research Resources
Abstract: Patients with Ewing s Sarcoma family of tumors with a large primary, a primary in the humerus, femur or trunk or those with metastatic disease at diagnosis, are at high risk for treatment failure. Recently, a very high-dose short-term VAC regimen was shown to have excellent anti-tumor activity and manageable toxicity in this group of patients. VAC is Vincristine (V), Doxorubicin (A), Cyclophosphamide (C). The investigators will build on this dose-intensive regimen by adding the cardioprotectant Dexrazoxane (dxr) and increasing the dose of A from 75 mg/m2 to 90 mg/m2 per course. In addition, ImmTher, an immune modulator which activates monocyte-mediated tumor cell killing, will be given to 2/3 of the patients following primary chemotherapy, surgery, and/or radiotherapy. ImmTher induced regression of lung and liver metastases in a Phase I study. Since the lung is a common site of metastasis in this disease, the goal is to activate pulmonary macrophages to destroy residual tumor cells. The aims of this randomized Phase II trial are 1) to determine if dose intensive VACdxr with or without ImmTher can improve the 2-year disease-free survival seen with standard VAC therapy; 2) to evaluate the feasibility and describe the toxicity associated with VACdxr; 3) to evaluate the feasibility and describe the toxicity of administering ImmTher on a weekly basis for one year; 4) to determine which therapy, VACdxr with Immther or VACdxr without ImmTher, is worthy of further evaluation. A maximum of 104 patients will be randomized. Patients will be stratified according to the presence of bony metastases.
Keywords: Ewing s tumor, cancer risk, combination antineoplastic therapy, cyclophosphamide, doxorubicin, drug screening /evaluation, human therapy evaluation, neoplasm /cancer chemotherapy, phosphatidylcholine, vincristine, bone neoplasm, clinical trial phase II /III /IV, cytotoxicity, drug administration rate /duration, leukocyte activation /transformation, liver neoplasm, lung neoplasm, macrophage, metastasis, monocyte, neoplasm /cancer remission /regression, neoplastic cell, skeletal disorder chemotherapy, clinical research, human subject
VACDXR W/ OR W/OUT IMMTHER FOR DIAGNOSED HIGH RISK EWINGS SARCOMA
Eugenie S Kleinerman, Professor And Head
University Of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225
Grant 5M01RR002558-140202 from National Center For Research Resources
Abstract: Patients with Ewing s Sarcoma family of tumors with a large primary, a primary in the humerus, femur or trunk or those with metastatic disease at diagnosis, are at high risk for treatment failure. Recently, a very high-dose short-term VAC regimen was shown to have excellent anti-tumor activity and manageable toxicity in this group of patients. VAC is Vincristine (V), Doxorubicin (A), Cyclophosphamide (C). The investigators will build on this dose-intensive regimen by adding the cardioprotectant Dexrazoxane (dxr) and increasing the dose of A from 75 mg/m2 to 90 mg/m2 per course. In addition, ImmTher, an immune modulator which activates monocyte-mediated tumor cell killing, will be given to 2/3 of the patients following primary chemotherapy, surgery, and/or radiotherapy. ImmTher induced regression of lung and liver metastases in a Phase I study. Since the lung is a common site of metastasis in this disease, the goal is to activate pulmonary macrophages to destroy residual tumor cells. The aims of this randomized Phase II trial are 1) to determine if dose intensive VACdxr with or without ImmTher can improve the 2-year disease-free survival seen with standard VAC therapy; 2) to evaluate the feasibility and describe the toxicity associated with VACdxr; 3) to evaluate the feasibility and describe the toxicity of administering ImmTher on a weekly basis for one year; 4) to determine which therapy, VACdxr with Immther or VACdxr without ImmTher, is worthy of further evaluation. A maximum of 104 patients will be randomized. Patients will be stratified according to the presence of bony metastases.
Keywords: Ewing s tumor, cancer risk, combination antineoplastic therapy, cyclophosphamide, doxorubicin, drug screening /evaluation, human therapy evaluation, neoplasm /cancer chemotherapy, phosphatidylcholine, vincristine, bone neoplasm, clinical trial phase II /III /IV, cytotoxicity, drug administration rate /duration, leukocyte activation /transformation, liver neoplasm, lung neoplasm, macrophage, metastasis, monocyte, neoplasm /cancer remission /regression, neoplastic cell, skeletal disorder chemotherapy, clinical research, human subject
Vasculogenesis In Ewing s Sarcoma: Useintherapy
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 5R01CA103986-03 from National Cancer Institute IRG: ZRG1
Abstract: Despite multiple changes in the chemotherapeutic approach for Ewing s sarcoma, the 2 year disease-free survival remains at 40-50% depending on disease site. Better understanding of the tumor biology may uncover therapeutic approaches. Using a nude mouse model, we demonstrated that Ewing s sarcoma cells overexpress VEGF and that bone marrow stem cells contribute to the development of new tumor vasculature as the tumor grows (a process known as vasculogenesis as opposed to angiogenesis). Approximately 10% of the new tumor vessels could be attributed to vasculogenesis. We further demonstrated the chemotactic capability of VEGF for bone marrow cells both in vitro (using Boyden Chambers) and in vivo (using matrigel-VEGF plugs). Together these data suggest that bone marrow cells travel to the tumor area in response to VEGF and subsequently contribute to the expansion of the tumor vasculature that is required to support the growing tumor. Our goal is to determine whether VEGF is the chemotactic stimulus, if suppressing VEGF has an impact on bone marrow cell migration and subsequent tumor vasculogenesis, and finally whether these bone marrow cells can be modified to deliver genes to the tumor area. We propose to (1) define the bone marrow cell subpopulations that contribute to this vasculogenesis process. (2) Determine whether cell division of migrated bone marrow cells contributes to vasculogenesis. (3) Determine whether tumor VEGF165 production influences tumor vasculogenesis. This will be done by inhibiting VEGF165 by siRNA. (4) Determine whether CD34+ (or mesenchymal cells as an alternative) can be used to deliver genes to the tumor area. Understanding the biology and the role that vasculogenesis plays in the development of Ewing s sarcoma may provide new therapeutic targets. Our goal is to identify whether VEGF165 is the chemotactic signal, to determine whether interfering with VEGF165 has an impact on the migration of bone marrow cells and explore whether these cells can be used to deliver genes to the tumor area.
Keywords: Ewing s tumor, angiogenesis, bone marrow, gene delivery system, gene therapy, hematopoietic stem cell, neoplastic growth, vascular endothelial growth factor, CD34 molecule, cell cycle, cell differentiation, cell migration, chemotaxis, cholecalciferol, interleukin 12, nonhuman therapy evaluation, SCID mouse, athymic mouse, clinical research, cord blood, flow cytometry, genetically modified animal, human tissue, immunocytochemistry, laboratory mouse, small interfering RNA
Project start date: 2004-07-01
Project end date: 2007-08-31
5R01CA103986-03 (2006): $241820
5R01CA103986-02 (2005): $247640
Vasculogenesis In Ewing s Sarcoma: Implications For Ther
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 1R01CA103986-01A1 from National Cancer Institute IRG: ZRG1
Abstract: Despite multiple changes in the chemotherapeutic approach for Ewing s sarcoma, the 2 year disease-free survival remains at 40-50% depending on disease site. Better understanding of the tumor biology may uncover therapeutic approaches. Using a nude mouse model, we demonstrated that Ewing s sarcoma cells overexpress VEGF and that bone marrow stem cells contribute to the development of new tumor vasculature as the tumor grows (a process known as vasculogenesis as opposed to angiogenesis). Approximately 10% of the new tumor vessels could be attributed to vasculogenesis. We further demonstrated the chemotactic capability of VEGF for bone marrow cells both in vitro (using Boyden Chambers) and in vivo (using matrigel-VEGF plugs). Together these data suggest that bone marrow cells travel to the tumor area in response to VEGF and subsequently contribute to the expansion of the tumor vasculature that is required to support the growing tumor. Our goal is to determine whether VEGF is the chemotactic stimulus, if suppressing VEGF has an impact on bone marrow cell migration and subsequent tumor vasculogenesis, and finally whether these bone marrow cells can be modified to deliver genes to the tumor area. We propose to (1) define the bone marrow cell subpopulations that contribute to this vasculogenesis process. (2) Determine whether cell division of migrated bone marrow cells contributes to vasculogenesis. (3) Determine whether tumor VEGF165 production influences tumor vasculogenesis. This will be done by inhibiting VEGF165 by siRNA. (4) Determine whether CD34+ (or mesenchymal cells as an alternative) can be used to deliver genes to the tumor area. Understanding the biology and the role that vasculogenesis plays in the development of Ewing s sarcoma may provide new therapeutic targets. Our goal is to identify whether VEGF165 is the chemotactic signal, to determine whether interfering with VEGF165 has an impact on the migration of bone marrow cells and explore whether these cells can be used to deliver genes to the tumor area.
Keywords: Ewing s tumor, angiogenesis, bone marrow, gene delivery system, gene therapy, hematopoietic stem cell, neoplastic growth, vascular endothelial growth factor, CD34 molecule, cell cycle, cell differentiation, cell migration, chemotaxis, cholecalciferol, interleukin 12, nonhuman therapy evaluation, RNA interference, SCID mouse, athymic mouse, clinical research, cord blood, flow cytometry, genetically modified animal, human tissue, immunocytochemistry, laboratory mouse, small interfering RNA
Project start date: 2004-07-01
Project end date: 2007-06-30
1R01CA103986-01A1 (2004): $247640
VASCULOGENESIS IN EWING´S SARCOMA: IMPLICATIONS FOR THERAPY
Eugenie S Kleinerman, Professor
University Of Texas Md Anderson Can Ctr, Unit 0176, Houston, Tx 77030-4009
Grant 5R01CA103986-06 from National Cancer Institute
Abstract: Despite multiple changes in chemotherapy over the past 15-20 years, the 2-year metastasis- free survival for Ewing´s sarcoma remains at 40% with a 3-year overall survival of 50%. Understanding the mechanisms that contribute to the growth of Ewing´s sarcoma may assist in the development of new therapeutic approaches. We demonstrated that Ewing´s tumor cell lines and primary patient tumor specimens overexpress VEGF with a shift from the membrane- bound 189 isoform to the soluble 165 isoform. VEGF165 has been shown to chemoattract stem cells. Using our Ewing´s sarcoma nude mouse model in a transplant setting we demonstrated that bone marrow (BM) cells migrate into the tumor, differentiate into endothelial cells and contribute to the formation of the tumor vasculature. We demonstrated that there are 2 distinct patterns of stem cell infiltration and 2 different phenotypes that migrate into the tumor. Murine Sca1+Gr1+ stem cells and human CD34+ cells co-localized to tumor vessels and differentiate into endothelial cells and pericytes. Murine Sca1-Gr1+ and human CD34- cells migrated deep in the tumor tissue away from tumor vessels and differentiated into macrophages. We demonstrated that pericytes and VEGF165 is responsible for the chemoattraction of these stem cells. This activity was not duplicated by VEGF189. Further investigations using VEGF165-siRNA support our hypothesis that these migrated stem cells play an important role in tumor growth and tumor vessel development. Taken together our data indicate that vasculogenesis, in addition to angiogenesis is involved in the expansion of the tumor vasculature contributing to about 10% of the vessels during the first week of tumor growth. We wish to continue investigating the vasculogenesis process, determine the importance of this process in both primary and metastatic tumor growth and investigate the mechanism(s) by which stem cells are attracted to specific tumor vascular areas. We propose to (1) determine whether BM-derived cells are integrated together with local endothelial cells to form tumor vessels and whether this is modified in the absence of VEGF165; (2) determine the importance of vasculogenesis to tumor growth and whether vasculogenesis can restore growth and vessel development in the absence of VEGF165; (3) determine whether NOTCH signaling, in specific DLL4, plays a role in the chemoattraction of stem cells to the Ewing´s tumor; (4) determine whether BM stem cells participate in the growth of Ewing´s metastases in the lung and bone. Understanding how vasculogenesis contributes to the growth and metastasis of Ewing´s sarcoma and ascertaining the chemotactic signals involved in this process may open up new therapeutic approaches to treat patients with this disease. This application will investigate how bone marrow (BM) stem cells contribute to the vasculature expansion that supports the growth of Ewing´s sarcoma and the mechanisms that control the migration of BM cells into the tumor. We will also determine whether BM stem cells contribute to the growth of Ewing´s metastases in the lung and bone. The survival rates for Ewing´s sarcoma have not improved for >20 years. Understanding how tumor vessels are formed may identify new therapeutic approaches for this type of cancer
Keywords: 22-Oxovincaleukoblastine; 2H-1, 3, 2-Oxazaphosphorin-2-amine, N, N-bis(2-chloroethyl)tetrahydro-, 2-oxide; 2H-1, 3, 2-oxazaphosphorin-2-amine, N, N-is(2-chloroethyl)tetrahydro-, 2-oxide; Address; Adjuvant Chemotherapy; Adriablastin; Adriablastine; Adriacin; Adriamycin PFS; Adriamycin RDS; Adriblastin; Adriblastina; Adriblastine; Adrimedac; Adventitial Cell; Area; Arteries; Athymic Nude Mouse; Binding; Binding (Molecular Function); Blood Vessel Tumor; Blood Vessels; Bone; Bone Marrow; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Metastasis; Bone and Bones; Bone cancer metastatic; Bones and Bone Tissue; Bony metastasis; CD34; CD34 gene; CTX; CXCL12 protein; CYCLO-cell; Carloxan; Cell Communication and Signaling; Cell Line; Cell Lines, Strains; Cell Locomotion; Cell Migration; Cell Movement; Cell Signaling; CellLine; Cells; Cellular Migration; Chemokine (C-X-C Motif) Ligand 12; Chemotherapy Protocol; Chemotherapy Regimen; Chemotherapy, Adjuvant; Chemotherapy, Cancer, General; Chemotherapy-Oncologic Procedure; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; Combination Chemotherapy Regimen; Combination Drug Therapy; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Confocal Microscopy; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamide; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; DOXO-CELL; Data; Development; Disease; Disorder; Doxolem; Doxorubin; Drug Therapy, Adjuvant; Editorial Comment; Editorial Comment (PT); Endothelial Cells; Endoxan; Endoxana; Enduxan; Ewing`s Family of Tumours; Ewing`s Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Ewing`s Tumor; Ewings sarcoma; Farmiblastina; Fosfaseron; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Generalized Growth; Genetic Intervention; Genoxal; Genuxal; Goals; Grant; Growth; Growth and Development; Growth and Development function; HPCA1; Human; Human, General; Infiltration; Intervention, Genetic; Intracellular Communication and Signaling; Investigation; Isoforms; Knock-out; Knockout; Laboratories; Ledoxina; Leurocristine; Ligands; Liposomal Adriamycin; Lung; Mammals, Mice; Man (Taxonomy); Man, Modern; Membrane; Metastasis; Metastasis to bone; Metastasis to the Lung; Metastasize; Metastatic Cancer to the Bone; Metastatic Neoplasm; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Lung; Metastatic Tumor; Metastatic Tumor to the Bone; Metastatic Tumor to the Lung; Metastatic malignant neoplasm to bone; Mice; Mice, Athymic; Mice, Nude; Mitoxan; Modeling; Molecular Biology, Gene Therapy; Molecular Interaction; Mother Cells; Motility; Motility, Cellular; Murine; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Neosar; Nude Mice; Osseous metastasis; Patients; Pattern; Pericapillary Cell; Pericytes; Perivascular Cell; Phenotype; Play; Polychemotherapy; Pre-B Cell Growth Stimulating Factor; Process; Procytox; Progenitor Cells; Protein Isoforms; Published Comment; Quimioterapia; RNA, Small Interfering; Research Specimen; Respiratory System, Lung; Reticuloendothelial System, Bone Marrow; Role; Rouget Cells; Rubex; SDF-1; SDF-1alpha; Sampling; Sdf1 protein; Secondary Neoplasm; Secondary Tumor; Secondary cancer of bone; Secondary malignancy of bone; Secondary malignant neoplasm of bone; Sendoxan; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skeletal metastasis; Small Interfering RNA; Solid Neoplasm; Solid Tumor; Specimen; Stem cells; Stromal Cell-Derived Factor 1; Survival Rate; Syklofosfamid; Technology; Therapeutic; Therapy, DNA; Tissue Growth; Transplantation; Tumor Biology; Tumor Cell Line; Tumor Cell Migration; Tumor Expansion; Tumor Tissue; VCR; VEGF(165); VEGF(165) protein, human; VEGF(189); VEGF(189) protein, human; VEGF165; VEGF165 protein, human; VEGF189; VEGF189 protein, human; VEGFs; Vascular Endothelial Growth Factors; Vascular Neoplasms; Vascular Tissue Tumor; Vascular Tumor; Vegf; Viewpoint; Viewpoint (PT); Vincaleukoblastine, 22-oxo-; Vincristine; Vincrystine; Zytoxan; adriamycin; angiogenesis; biological signal transduction; blood vessel neoplasm; bone; bone neoplasm secondary; cancer chemotherapy; cancer metastasis; cancer type; cell motility; chemotherapy; combination pharmacotherapy; cultured cell line; disease/disorder; gene therapy; genetic therapy; hIRH; human stem cells; improved; macrophage; membrane structure; migration; mouse model; notch; notch protein; notch receptors; novel; novel therapeutic intervention; ontogeny; overexpression; oxovincaleukoblastine; pulmonary; pulmonary metastasis; siRNA; social role; stromal cell-derived factor-1alpha; transplant; tumor; tumor growth; vascular; vasculogenesis
Project start date: 2003-12-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: PA-07-070
5R01CA103986-06 (2010): $254023
5R01CA103986-05 (2009): $114400
Sponsored Links Excellgen http://Excellgen.com
2R01CA103986-04A1 (2008): $254023
LIPOSOME AND POLYCATIONIC GENE THERAPY FOR OSTEOSARCOMA
Eugenie S Kleinerman, Professor
University Of Texas Md Anderson Can Ctr, Unit 0176, Houston, Tx 77030-4009
Grant 3R01CA042992-24S1 from National Cancer Institute
Abstract: Despite multiple changes in adujvant chemotherapy, the 2-year metastasis-free survival in osteosarcoma (OS) has remained stagnant at 65-70% for the past 10 years. The lung is the most common and often the only site of metastases. Our laboratory has focused on understanding the mechanisms involved in OS metastasis to the lung and in identifying novel ways to treat OS pulmonarymetastases. Using our experimental humanOS lung metastasis nude mouse model we demonstrated that Fas expression correlates inversely with metastatic potential. We hypothesized that because FasL is constitutively expressed in the lung, that OS cells expressing high levels of Fas will be eliminated upon migration into the lung, whereas those with low or no Fas expression will evade this form of host resistance. We also demonstrated that IL-12 upregulated tumor Fas expression in vitro, altered metastatic potential and that the IL-12 gene could be delivered by aerosol using polyethyinemine (PEI) as a vector delivery system. Aerosol PEIIL-12 upregulated tumor Fas in vivo and induced regression of established microscopic pulmonary metastases. We also demonstrated that aerosol delivery of liposome-encapsulated 9-nitrocamptothecin (L-9NC) upregulated tumor Fas expression and resulted in eradication of OS lung metastases. A phase I trial in adults using aerosol L-9NC demonstrated the feasibility of aerosol chemotherapy. No children or adolescents were treated in this phase I trial. We now propose to (1) perform a phase I/II clinicaltrial with aerosol L-9NC in patients 10-25 years old with metastases in the lung; (2) determine whether inhibiting Fas signalling impacts tumor cell clearance, cell proliferation and the metastatic potential of OS cells to the lung; (3) determine whether the Fas pathway is critical for both aerosol IL-12 and L-9NC activity in vivo. Together these investigations should give an indication of the importance of the Fas pathway in the metastatic process of OS and in the therapeutic efficacy of both aerosol L-9NC and PEIIL-12 gene therapy. The long term objectives are to develop aerosol therapy for metastatic OS and other tumors that relapse in the lung
Keywords: 0-11 years old; 21+ years old; 9-NC; 9-nitrocamptothecin; Adjuvant Chemotherapy; Adolescent; Adolescent Youth; Adult; Adverse effects; Aerosol Drug Therapy; Aerosols; Antimorphic mutation; Athymic Nude Mouse; Bone Sarcoma; Cell Communication and Signaling; Cell Growth in Number; Cell Line; Cell Lines, Strains; Cell Multiplication; Cell Proliferation; Cell Signaling; CellLine; Cells; Cellular Proliferation; Chemotherapy Protocol; Chemotherapy Regimen; Chemotherapy, Adjuvant; Chemotherapy, Cancer, General; Chemotherapy-Oncologic Procedure; Child; Child Youth; Childhood; Children (0-21); Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Combination Chemotherapy Regimen; Coughing; Data; Death Domain; Dominant Negative; Dominant-Negative Mutant; Dominant-Negative Mutation; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drug Therapy, Adjuvant; Drug Therapy, Aerosol; Early-Stage Clinical Trials; Edodekin Alfa; Encapsulated; Fatigue; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genetic Intervention; Grant; Host resistance; Human; Human, Adult; Human, Child; Human, General; IL-12; IL-12 gene; IL12; In Vitro; Interleukin-12; Interleukin-12 Gene; Intervention, Genetic; Intracellular Communication and Signaling; Investigation; Knockout Mice; Laboratories; Lack of Energy; Liposomal; Liposomes; Lung; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediator; Mediator of Activation; Mediator of activation protein; Metastasis; Metastasis to the Lung; Metastasize; Metastatic Neoplasm; Metastatic Neoplasm to the Lung; Metastatic Osteogenic Sarcoma; Metastatic Osteosarcoma; Metastatic Tumor; Metastatic Tumor to the Lung; Metastatic to; Methods; Mice; Mice, Athymic; Mice, Knock-out; Mice, Knockout; Mice, Nude; Microscopic; Modeling; Molecular Biology, Gene Therapy; Murine; Mus; NKSF; Natural Killer Cell Stimulatory Factor; Neoplasm Metastasis; New Agents; Nitro camptothicin; Nitrocamptothecin; Nude Mice; Null Mouse; Organ; Osseous Sarcoma; Pathway interactions; Patients; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Play; Pre-Clinical Model; Preclinical Models; Quimioterapia; Relapse; Respiratory System, Lung; Role; Sarcoma, Osteogenic; Secondary Neoplasm; Secondary Tumor; Signal Transduction; Signal Transduction Pathway; Signal Transduction Systems; Signaling; Site; Skeletal Sarcoma; Sore Throat; Stream; System; System, LOINC Axis 4; Therapeutic; Therapy, DNA; Toxic effect; Toxicities; Treatment Efficacy; Treatment Side Effects; Tumor Cell; Tumor Cell Migration; Up-Regulation; Up-Regulation (Physiology); Upregulation; Wheezing; Wheezings; adult human (21+); adult youth; aerosol therapy; base; biological signal transduction; cancer chemotherapy; cancer metastasis; chemotherapy; children; clinical investigation; cultured cell line; gene therapy; genetic therapy; in vivo; juvenile; juvenile human; metastatic process; migration; mouse model; neoplastic cell; new approaches; novel; novel approaches; novel strategies; novel strategy; osteochondrosarcoma; osteoid sarcoma; osteosarcoma; overexpression; pathway; pediatric; phase 1 study; phase 1 trial; phase I trial; protocol, phase I; pulmonary; pulmonary metastasis; response; side effect; social role; therapeutic efficacy; therapeutically effective; therapy adverse effect; treatment adverse effect; tumor; vector; wheeze; young adult; youngster
Project start date: 1986-08-01
Project end date: 2010-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
3R01CA042992-24S1 (2010): $92714
2R01CA042992-20A1 (2006): $271800
2R01CA042992-15 (2000): $339750
CHEMO/IMMUNOTHERAPY FOR HIGH RISK EWINGS SARCOMA
Eugenie S Kleinerman, Professor And Head
Surgical Oncology & Cell Bioluniversity Of Texas Md Anderson Can Ctr
cancer Center
houston, Tx 770304009
Grant 5R01CA082606-03 from National Cancer Institute IRG: ZRG1
Abstract: adapted verbatim from the investigator´s ) Patients with Ewing´s sarcoma family of tumors who are at high-risk for relapse are those with metastic disease at diagnosis, with a primary tumor of the humerus, femur or trunk, or with localized but bulky (>8cm) disease at the time of diagnosis. At 2 y>60% will have recurrence in lung, bone or bone marrow. Recently, a very high-dose short-term VAC regimen was shown to have excellent anti-tumor activity and manageable toxicity in this high-risk group of patients. The randomized phase II trial described in this proposal builds on this dose-intensive regimen by adding the cardioprotectant Dexrazoxane (dxr) and increasing the dose of A from 75mg/m(2) to 90m/m(2) per course. In addition ImmTher, a new immune modulator that activates monocyte-mediated tumor cell killing will be given to 2/3 of the patients following completion of all primary chemotherapy, surgery and/or radiotherapy. ImmTher is a lipophilic disaccharide dipeptide derivative of muramyl dipeptide encapsulated into liposomes. When given i.v. ImmTher induced regression of lung and liver metastases in a Phase I study. Since the lung is a common site of metastasis in Ewing´s Sarcoma, our goal is to activate pulmonary macrophages to destroy residual tumor cells. Patients will be stratified according to the presence of bony metastases and then randomized at study entry in a 21 ratio in favor of receiving ImmTher. ImmTher will be given weekly for 52 weeks. This 21 randomization strategy was requested by the FDA during the initial protocol development phase so that more information on the toxicity of long-term ImmTher administration could be obtained. The specific aims of this phase II trial are (I) determine whether ImmTher given following dose-intensive VAC can improve the 2-yr disease-free survival and 3-yr long term survival in this high-risk group. (II) Evaluate the immunomodulatory activity of ImmTher in patients following dose- intensive chemotherapy. Plasma TNGa, IL-6, IL-8, IL1a, IL-1B, neopterin, IL-12, IFNy and peripheral blood monocyte tumoricidal activity will be monitored to this end before, during and after ImmTher treatment. (III) As a pilot study we will also monitor serum VEGF levels in all patients throughout the treatment period and during follow-up visits. Our hypothesis is that VEGF may contribute to the growth and invasion of Ewing´s sarcoma and that serum VEGF levels may predict relapse
Keywords: Ewing`s tumor, combination cancer therapy, human therapy evaluation, immunomodulator, neoplasm /cancer chemotherapy, neoplasm /cancer immunotherapy, vascular endothelial growth factor alveolar macrophage, cardiovascular agent, clinical trial phase II /III /IV, cyclophosphamide, dosage, doxorubicin, drug screening /evaluation, metastasis, neoplasm /cancer relapse /recurrence, vincristine clinical research, human subject
Project start date: 1999-07-01
Project end date: 2002-06-30
5R01CA082606-03 (2001): $143532
5R01CA082606-02 (2000): $140628
1R01CA082606-01 (1999): $137807
Vasculogenesis In Ewing´s Sarcoma: Implications For Therapy
Eugenie S Kleinerman, Professor And Head
Pediatricsuniversity Of Texas Md Anderson Can Ctr
cancer Center
houston, Tx 770304009
Grant 2R56CA103986-04 from National Cancer Institute IRG: ZRG1
Project start date: 2003-12-01
Project end date: 2008-08-31
2R56CA103986-04 (2007): $241820
Liposome And Polycationic Gene Therapy For Osteosarcoma
Eugenie S Kleinerman, Professor And Head
University Of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 770304009
Grant 3R01CA042992-21S1 from National Cancer Institute IRG: DT
Project start date: 1986-08-01
Project end date: 2010-12-31
3R01CA042992-21S1 (2007): $41323
VACDXR W/ OR W/OUT IMMTHER FOR NEWLY DIAGNOSED HIGH RISK EWINGS SARCOMA
Eugenie S Kleinerman, Professor And Head
University Of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225
Grant 5M01RR002558-180202 from National Center For Research Resources
Keywords: Ewing s tumor, cancer risk, combination cancer therapy, cyclophosphamide, doxorubicin, drug screening /evaluation, human therapy evaluation, neoplasm /cancer chemotherapy, phosphatidylcholine, vincristine, bone neoplasm, cytotoxicity, drug administration rate /duration, leukocyte activation /transformation, liver neoplasm, lung neoplasm, macrophage, metastasis, monocyte, neoplasm /cancer remission /regression, neoplastic cell, skeletal disorder chemotherapy, clinical research, human subject
Sponsored Links Excellgen http://Excellgen.com
LIPOSOME THERAPY--A POTENTIAL ADJUVANT FOR OSTEOSARCOMA
Eugenie S Kleinerman, Professor And Head
Cell Biologyuniversity Of Texas Md Anderson Can Ctr
cancer Center
houston, Tx 770304009
Grant 2R01CA042992-11 from National Cancer Institute IRG: ET
Project start date: 1986-08-01
Project end date: 2000-03-31
2R01CA042992-11 (1996): $169204