BMTP-11 found to delay progression of osteosarcoma


Osteosarcoma is a bone tumor, with a peak in the late adolescent and young adult period. Despite great advances in treating the disease, many challenges still remain and particularly in the management of high-grade osteosarcomas.

Incidence

Osteosarcoma is a relatively rare cancer that its overall incidence is low; however, it is the most common primary bone malignancy and accounts for about 2.4% of all malignancies that happen in children. Among childhood cancers, osteosarcoma occurs eighth in general incidence. Fig. 1 below shows the top nine childhood cancers and their percentage among all pediatric cancers[1].

Fig. 1 Top 9 Pediatric Cancers

Rank Type of cancer Percentage
1 Leukemia 30%
2 Brain and other nervous system cancers 22.3%
3 Neuroblastoma 7.3%
4 Wilms tumor 5.6%
5 Non-Hodgkin lymphoma 4.5%
6 Rhabdomyosarcoma 3.1%
7 Retinoblastoma 2.8%
8 Osteosarcoma 2.4%
9 Ewing sarcoma 1.4%

Pathogenesis

Several risk factors for osteosarcoma have been identified. Firstly, radiation from the treatment of another cancer can trigger osteosarcoma. This is because radiotherapy can damage the DNA inside cells. Secondly, certain non-cancerous bone diseases appear to increase the risk of developing osteosarcoma. An example is Paget disease of the bone. Thirdly, there are a number of inherited genetic conditions that predispose affected individuals to a variety of osteosarcoma. These include hereditary retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomson syndrome, and Bloom and Werner syndromes. Finally, age and gender also have an impact on the risk of the development of osteosarcoma. People aged 10 to 30 or over the age of 60 are more likely to develop osteosarcoma. Osteosarcoma is more common in males than in females.

At the molecule level, the Wnt pathway has long been suspected of correlating with osteosarcoma. Some studies have shown that aberrant activation of canonical Wnt signaling contributes to osteosarcoma progression and secreted Wnt antagonists decreases tumorigenesis and metastasis[2]. However, other studies have also reported opposing findings: loss of Wnt/β-catenin pathway activity, which is required for osteoblast differentiation, may contribute to osteosarcoma development[3]. Given that Wnt signaling pathways play divergent roles during development, normal homeostasis and disease, these pathways should be further explored for potential targeted therapies.

Treatment

Over the last three decades, remarkable advances have been made in the management of osteosarcoma, which saves many lives. There are many different types of treatment available for treating osteosarcoma. The most commonly used are surgery and chemotherapy, and there are also other treatment options and some are in development or being tested. Which type you receive depends on disease severity, tumor size, location, the patient's age, and other factors. Examples of treatment options include:

1. Surgery

The main goal of surgery is to remove all of the cancer. Additionally, surgery is also performed for bone graft or prosthesis implant to replace the bone that's lost, which helps maintain function and minimize disability.

Knowledge of osteosarcoma has increased and imaging techniques and devices have improved. These advances allow doctors to better locate and evaluate the tumor and plan surgeries to remove all of the tumors while causing less damage to normal tissues. For instance, doctors will determine whether the patient is a suitable candidate for limb-sparing surgery, amputation, or rotationplasty.

Besides, internal prostheses have also improved. Now the new internal prostheses can be expanded without additional surgery. This is very important for children in the period of growth and development.

2. Chemotherapy

Chemotherapeutic agents kill cancer cells, reducing tumor size. These drugs are recommended to be used before and after surgery for osteosarcoma.

For high-grade osteosarcoma, the current standard therapy is an aggressive combination of high-dose methotrexate with doxorubicin and cisplatin in the neoadjuvant and adjuvant settings, complemented by surgery when possible[4].

Some existing and novel chemotherapeutic agents are being tested in clinical trials. Scientists want to find the best combinations of these drugs and to determine the optimal dosage and timing of administration

Osteosarcoma may spread to different parts of the body but most often it spreads to the lungs. Inhaled forms of some chemotherapeutic drugs, such as cisplatin[5] and sargramostim (a man-made version of the protein GM-CSF)[6], are being tested for treatment osteosarcoma that has already spread to the lung.

3. Radiotherapy

Radiotherapy, or called radiation therapy, uses a controlled dose of radiation to kill cancer cells or damage them so they cannot grow, multiply or spread. Radiation can be in the forms of x-ray beams, electron beams, or gamma rays.

Radiotherapy for osteosarcoma is uncommon because the disease is relatively resistant to radiation. To kill osteosarcoma cells, high-dose radiation is needed but this can cause unwanted side effects. These shortcomings limit the application of radiotherapy in the management of osteosarcoma. However, this situation may change if new forms of radiotherapy could deliver high-dose of radiation precisely to the tumor while doing less damage to the nearby normal tissues.

4. Targeted therapy

Targeted therapies block the growth of cancer cells by interfering with specific targeted molecules that are critical for tumor development or progression.

A class of targeted therapy is monoclonal antibodies (mAb). One example of this class is dinutuximab, which is directed against a substance GD2. Clinical trials of dinutuximab in treatment of osteosarcoma are underway.

In addition, drugs that have antiangiogenic effects or target mTOR signaling pathway are also be studied for osteosarcoma management.

Besides, some targeted therapies do not target cancer cells, but instead, target bone cells. For instance, the antibody therapy denosumab targets a protein that helps bones grow, known as the RANKL protein. It is now being studied for use against osteosarcoma.

Prognosis

According to estimates, death rates for osteosarcoma have been declining by about 1.3% per year. For patients with localized osteosarcomas, the overall 5-year survival rate is 60%-70%, but for patients with metastatic disease, the 5-y survival rate is much lower 20%-30%, and with few therapeutic options available.

There is a gender difference in survival rates. Age is another factor that influence survival: the elderly appear to have the worst survival. Complete removal of tumors by surgery is critical for survival. Tumor size and location, presence o metastases, chemotherapy regimen, and many other factors also impact prognosis.

The age of the patient is correlated with the survival, with the poorest survival among older patients. Complete surgical excision is important to ensure an optimum outcome. Tumor staging, the presence of metastases, local recurrence, chemotherapy regimen, anatomic location, size of the tumor, and percentage of tumor cells destroyed after neoadjuvant chemotherapy have effects on the outcome.

Research

Now a research team consisting of scientists from the University of Texas M.D. Anderson Cancer Center, University of New Mexico Comprehensive Cancer Center, University of Michigan Comprehensive Cancer Center, and Harvard Medical School has identified a marker of osteosarcoma progression and poor prognosis. The study, detailed in the Proceedings of the National Academy of Sciences, reveals that the IL-11 receptor α subunit (IL-11Rα) and its ligand IL-11 are increased in human metastatic osteosarcoma cell lines, and this enhances the growth, proliferation, and invasion of tumor cells in vitro and promotes the formation of lung metastases in vivo. These results indicate that IL-11Rα may act as a marker of disease progression and poor prognosis in patients with osteosarcoma and targeting IL-11Rα may be an approach to inhibit osteosarcoma metastasis[4].

Previous studies have revealed a potential link between the IL-11:IL-11Rα axis and osteosarcoma. In this work, the team further explored this axis' role. Using multiple analytic methods like immunohistochemistry (IHC), the team measured the levels of IL-11Rα expression in tissue samples from osteosarcoma patients and found that IL-11Rα levels in metastases were much higher than that in primary tumors. Correlation studies showed that patients who had higher IL-11Rα in their primary tumors were more likely to have a worse prognosis. Further investigation revealed that IL-11, the ligand of IL-11Rα, was expressed at higher levels in metastatic cell lines than in nonmetastatic cells. Collectively, these findings support the potential of IL-11Rα as a biomarker of progression of osteosarcoma.

Next, the team tested the effect of an IL-11Rα-targeting drug, called BMTP-11, in an orthotopic model of human metastatic osteosarcoma. Results showed that BMTP-11 delayed primary tumor growth and secondary metastatic spread of human osteosarcoma cells in the animals. Furthermore, this effect was enhanced when BMTP-11 was used in combination with the chemotherapy medication gemcitabine. BMTP-11 is still in development, and more research is needed to evaluate its efficacy in osteosarcoma[4].

Overall, the study supports that targeting IL-11Rα may be a therapeutic intervention for osteosarcoma and underscores the potential of BMTP-11 as a therapeutic agent for osteosarcoma. Valerae Lewis, first author of the study and a researcher at the University of Texas M.D. Anderson Cancer Center, noted that BMTP-11 attacks the tumor without affecting other tissues.

Reference:
[1] Giulia Ottaviani et al, The epidemiology of osteosarcoma. Cancer Treatment and Research (2009).
[2] Elyssa M. Rubin et al, Wnt Inhibitory Factor 1 Decreases Tumorigenesis and Metastasis in Osteosarcoma, Molecular Cancer Therapeutics (2010).
[3] Yongping Cai et al, Inactive Wnt/β‐catenin pathway in conventional high‐grade osteosarcoma, Journal of Pathology (2009).
[4] Valerae O. Lewis et al, BMTP-11 is active in preclinical models of human osteosarcoma and a candidate targeted drug for clinical translation, Proceedings of the National Academy of Sciences (2017).
[5] Alexander J. Chou et al, Inhaled lipid cisplatin (ILC) in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung, Pediatric Blood & Cancer (2012).
[6] Carola A.S. Arndt et al, Inhaled Granulocyte-Macrophage Colony Stimulating Factor for First Pulmonary Recurrence of Osteosarcoma: Effects on Disease-Free Survival and Immunomodulation. A Report From the Children's Oncology Group, Clinical Cancer Research (2010).
 

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