A Novel Agent to Suppress Tumor Growth in Bone, Prevent Cachectic Muscle Loss and Preserve Skeletal Integrity

一种抑制骨肿瘤生长、防止恶病质肌肉损失并保持骨骼完整性的新型药物

• 批准号: 10454796
• 负责人: JOHN M CHIRGWIN
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454796
• 关键词: Adipocytes; Age; Agonist; Automobile Driving; Biological Assay; Biology; Bone Diseases; Bone Pain; Bone Resorption; Bone remodeling; Breast; Breast Cancer Cell; Breast Cancer Model; Cachexia; Cancer Control; Cancer Etiology; Cartoons; Cattle; Cell Line; Cells; Clinical; Clinical Trials; Coculture Techniques; Coupled; Cyclic AMP; Data; Disseminated Malignant Neoplasm; Fatty acid glycerol esters; Financial Hardship; GTP-Binding Proteins; Genes; Growth; Health; Human; Hypercalcemia; Hypercalcemia of Malignancy; Immunocompetent; In Vitro; Incidence; Individual; Lead; Ligands; Luciferases; Lytic Metastatic Lesion; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Modeling; Multiple Myeloma; Mus; Muscle; Muscular Atrophy; Myalgia; Neoplasm Metastasis; Organ; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteolysis; Osteolytic; Osteoporosis; Pain; Parathyroid Neoplasms; Pathological fracture; Patients; Peptides; Preclinical Testing; Prevention; Production; Prostate; Quality of life; Sensory; Signal Transduction; Skeletal Muscle; Societies; TNFSF11 gene; Testing; Transforming Growth Factor beta; Tumor Burden; Tumor-Secreted Protein; Xenograft Model; Yin; advanced breast cancer; analog; angiogenesis; beta-arrestin; bone; bone cell; bone health; bone loss; bone preservation; bone repair; cancer cachexia; cancer cell; cancer clinical trial; cancer site; clinically relevant; improved; in vivo; malignant breast neoplasm; mouse model; neoplastic cell; nerve supply; neutralizing antibody; novel; osteosarcoma; parathyroid hormone-related protein; patient population; prevent; receptor; response; skeletal; skeletal muscle wasting; skeletal preservation; success; targeted treatment; tumor; tumor growth

ABSTRACT: Over 85% of patients with advanced cancers of breast and prostate suffer from incurable bone metastases. Osteoclast activation and osteoblast suppression lead to bone loss, pathologic fractures, hypercalcemia and bone pain, often accompanied by loss of skeletal muscle (cachexia). Current therapies target osteoclasts and have limited effects on tumor growth, while not restoring lost bone or muscle. Tumor-secreted parathyroid hormone-related protein, PTHrP, is a major causal agent of bone destruction by inducing expression of RANKL to increase osteoclast number and function. TGFβ, released during bone resorption, stimulates breast cancer production of PTHrP [Yin et al, 1999], driving a vicious cycle of bone metastases [Chirgwin & Guise, 2000; Kakonen et al, 2002]. PTHrP stimulates growth of PTH1R receptor- expressing tumors and indirectly causes cancer cachexia via reprogramming of adipocytes [Kir & Spiegelman, 2016]. It causes hypercalcemia of malignancy, stimulates angiogenesis and cancer bone pain. We believe the deleterious actions of tumor PTHrP can be blocked by a unique PTH1R ligand, while having beneficial anabolic effects on bone - which cannot be achieved with PTHrP-neutralizing antibody. [D-Trp12,Tyr34]-bovine-PTH(7- 34), bPTH7-34DD, is a unique inverse agonist of G protein-coupled signaling by PTH1R, decreasing cAMP, while activating β-arrestin signaling. It increases bone formation without causing hypercalcemia or osteolysis [Maudsley et al, 2015]. Our data showed anti-osteolytic and anti-tumor actions of bPTH7-34DD in co-cultures of breast cancer with mouse bone. It also countered adipocyte gene changes associated with cancer cachexia. We hypothesize that bPTH7-34DD will: 1) Inhibit the vicious cycle of osteolytic bone metastases by suppressing osteolysis & tumor growth; 2) Decrease cancer cachexia by blocking white-to-brown adipocyte conversion in bone; 3) Preserve bone health by stimulating new bone formation; 4) Effectively treat osteolytic tumors due breast cancer. 5) Be effective against other PTHrP-secreted tumor types. bPTH7-34DD will be tested in xenograft models of breast cancer bone metastasis, in prevention and treatment settings. The mechanism of bPTH7-34DD signaling will be tested in ex vivo co-cultures of cancer cells with mouse bones and in bone and fat cell lines and 1o cells and with bones and cells from wt & β-arrestin k/o (βarr2-/-) mice. Specific Aim 1: a) Determine growth effects ex vivo of bPTH7-34DD on tumor cells; b) Determine the mechanism of action of on i) Osteoblasts (Obs), osteoclasts (Ocs), & osteocytes (Ots); ii) On adipocytes; c) Test if responses to bPTH7-34DD require β-arrestin, using bones & cells from βarr2-/- mice; d) Test if bPTH7-34DD blocks growth in bone and osteolysis ex vivo with prostate and lung cancer and multiple myeloma cells Specific Aim 2: Test bPTH7-34DD in vivo for significant effects on: a) Tumor burden; b) Osteolytic lesions; c) Bone loss/formation systemically and adjacent to tumor; d) Skeletal muscle. Significance: bPTH7-34DD could be rapidly brought into clinical trials for cancer bone metastasis. Similar PTH & PTHrP peptides are used to treat osteoporosis. Benefit may extend to other PTHrP-expressing cancers that metastasize to bone, including multiple myeloma, which also colonizes bone and causes osteolysis. Technical Approaches: The project uses co-cultures of cancer cells with mouse bones, called EVOCA (ex vivo organ co-culture assay). Tumor growth is assayed by secreted Gaussia luciferase (gLuc) from stably transduced cancer cells. Changes in bone and MM genes are quantified by mouse- and human-specific qPCR. Two mouse models of breast cancer bone metastases will be used for preclinical testing. Consultants: Dr. Louis Luttrell is a world expert in PTH signaling and deciphered the actions of bPTH7-34DD. Dr. Teresa Zimmers is an expert in cancer cachexia. Dr. Jesus Delgado-Calle is an expert in osteocyte biology and osteocyte:adipocyte interactions in myeloma. Dr. David Roodman is a world expert on myeloma bone disease.

摘要：超过85%的晚期乳腺癌和前列腺癌患者患有无法治愈的骨癌

项目成果

DREAMM-2: Indirect Comparisons of Belantamab Mafodotin vs. Selinexor + Dexamethasone and Standard of Care Treatments in Relapsed/Refractory Multiple Myeloma.

• DOI: 10.1007/s12325-021-01884-7
• 发表时间: 2021-11
• 期刊: Advances in therapy
• 影响因子: 3.8
• 作者: Prawitz T;Popat R;Suvannasankha A;Sarri G;Hughes R;Wang F;Hogea C;Ferrante SA;Gorsh B;Willson J;Kapetanakis V
• 通讯作者: Kapetanakis V

Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study.

• DOI: 10.1002/cncr.33809
• 发表时间: 2021-11-15
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Lonial S;Lee HC;Badros A;Trudel S;Nooka AK;Chari A;Abdallah AO;Callander N;Sborov D;Suvannasankha A;Weisel K;Voorhees PM;Womersley L;Baron J;Piontek T;Lewis E;Opalinska J;Gupta I;Cohen AD
• 通讯作者: Cohen AD

Belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma in heavily pretreated patients: a US cost-effectiveness analysis.

Belantamab mafodotin 用于治疗经过大量治疗的患者的复发/难治性多发性骨髓瘤：美国成本效益分析。

• DOI: 10.1080/17474086.2021.1970522
• 发表时间: 2021
• 期刊: Expert review of hematology
• 影响因子: 2.8
• 作者: Nikolaou,Andreas;Ambavane,Apoorva;Shah,Anshul;Ma,Wenkang;Tosh,Jon;Kapetanakis,Venediktos;Willson,Jenny;Wang,Feng;Hogea,Cosmina;Gorsh,Boris;Gutierrez,Ben;Sapra,Sandhya;Suvannasankha,Attaya;Samyshkin,Yevgeniy
• 通讯作者: Samyshkin,Yevgeniy