BMTP-11 is active in preclinical models of human osteosarcoma and a candidate targeted drug for clinical translation

Abstract

Osteosarcoma occurs predominantly in children and young adults. High-grade tumors require multidisciplinary treatment consisting of chemotherapy in the neoadjuvant and adjuvant settings, along with surgical intervention. Despite this approach, death from respiratory failure secondary to the development and progression of pulmonary metastases remains a significant problem. Here, we identify the IL-11 receptor α subunit (IL-11Rα) as a cell surface marker of tumor progression that correlates with poor prognosis in patients with osteosarcoma. We also show that both IL-11Rα and its ligand, IL-11, are specifically up-regulated in human metastatic osteosarcoma cell lines; engagement of this autocrine loop leads to tumor cell proliferation, invasion, and anchorage-independent growth in vitro. Consistently, IL-11Rα promotes lung colonization by human metastatic osteosarcoma cells in vivo in an orthotopic mouse model. Finally, we evaluate the IL-11Rα-targeted proapoptotic agent bone metastasis-targeting peptidomimetic (BMTP-11) in preclinical models of primary intratibial osteosarcomas, observing marked inhibition of both tumor growth and lung metastases. This effect was enhanced when BMTP-11 was combined with the chemotherapeutic drug gemcitabine. Our combined data support the development of approaches targeting IL-11Rα, and establish BMTP-11 as a leading drug candidate for clinical translation in patients with high-risk osteosarcoma.BMTP-11 | IL-11Rα | osteosarcoma | mouse models | target therapy O steosarcoma is a tumor of bone with peak incidence occurring at age 10-20 y (1). Over the past quarter century, the 5-y survival rate has remained stagnant at ∼60-65% for patients with primary osteosarcoma and ∼20-25% for patients with metastatic disease (2), with few therapeutic options available. The current standard of care for high-grade osteosarcoma is an aggressive combination of high-dose methotrexate with doxorubicin (Adriamycin) and cisplatin (MAP) in the neoadjuvant and adjuvant settings, complemented by surgery when possible (2). Systemic treatment options have remained unchanged for the last 30 y. With the exception of mifamurtide (3, 4), which has been approved for use in the European Union and Israel-but, unfortunately, not the United States-the pipeline of cytotoxic drugs against osteosarcoma has essentially been dry. Recently, the EURAMOS-1 clinical trial demonstrated that the addition of ifosfamide plus etoposide to standard MAP (MAPIE) did not affect overall survival in patients with poor response (defined as ≤90% tumor necrosis to induction therapy), whereas PEGylated IFN alfa-2b maintenance provided only a modest (nonsignificant) improvement in the event-free survival of patients with good response (5).The widespread use of gemcitabine in sarcoma management, along with encouraging initial reports of gemcitabine plus docetaxel (GEMDOX) in pediatric osteosarcoma, prompted a formal evaluation in clinical trials. Despite some controversy, this regimen has been recently reported as somehow active against relaps...

IL-6 family cytokines: Key inflammatory mediators as biomarkers and potential therapeutic targets

“…Bone metastasis-targeting peptidomimetic (BMTP-11) directed against IL-11Rα retards primary tumor growth and lung metastasis in preclinical models of human osteosarcoma. BMTP-11 in combination with gemcitabine shows better outcomes than BMTP-11 alone [59]. Similarly, targeting IL-11Rα in combination with doxorubicin therapeutically improves the effect of chemotherapy in high grade Type I endometrioid cancer [60].…”

Fructose-coated Angstrom silver inhibits osteosarcoma growth and metastasis via promoting ROS-dependent apoptosis through the alteration of glucose metabolism by inhibiting PDK

“…Osteosarcoma is a common malignant bone tumor in children and young adults with a high rate of recurrence and a strong tendency to metastasize to distant organs such as the lungs 1 - 3 . Current treatment options for osteosarcoma mainly include neoadjuvant chemotherapy, tumor amputation and postoperative chemotherapy, which enhance the survival rate of patients with osteosarcoma 1 - 3 . Nevertheless, death from respiratory failure due to lung metastases remains a significant problem 1 .…”

“…Current treatment options for osteosarcoma mainly include neoadjuvant chemotherapy, tumor amputation and postoperative chemotherapy, which enhance the survival rate of patients with osteosarcoma 1 - 3 . Nevertheless, death from respiratory failure due to lung metastases remains a significant problem 1 . Moreover, the use of chemotherapeutic agents (cisplatin, doxorubicin, methotrexate, etc. )…”

Treating osteosarcoma with CAR T cells

“…Furthermore, IL11Ra expression has been demonstrated in lung metastasis from OS patients, whereas almost no, or poor expression was observed in healthy surrounding tissues . Recently, a correlation between cancer progression and IL‐11Ra activity was demonstrated using patient biopsies and metastatic versus non‐metastatic cell lines . This suggests that IL11Ra could be essential for tumour development.…”

“…The novelty in the targeting of IL‐11Ra resides in the strategy that was used to discover it: A combinatorial phage library was screened, and a cyclic nonapeptide was isolated and shown to specifically and selectively bind to the receptor . This peptide was then synthesized in tandem to a peptidomimetic motif previously shown to trigger cell death by mitochondrial membrane disruption has followed its preclinical development with the name BMTP‐11 for OS and other cancer types . A few years after its isolation, Huang and colleagues combined this peptide to a CAR scaffold construct (Figure ) and showed that it had the ability to redirected T cells towards OS .…”