Where Are We Now?
Conventional primary osteosarcoma is the most-common malignant bone tumor. As an aggressive neoplasm, it often affects young individuals, potentially taking years off patients’ lives . Standard chemotherapy and sophisticated surgical techniques have led to an improved prognosis, enabling complete tumor resection with wide margins and limb salvage in most patients. However, patients with limited response to chemotherapy or with distant metastases still have a poor prognosis .
In the age of molecular medicine and precision oncology, the standard chemotherapy regimen for osteosarcoma seems somewhat outdated. Our classification systems may need to be revised as well, particularly a few histomorphological subtypes under the WHO classification system (such as osteoblastic or chondroblastic osteosarcoma), which seem to have no prognostic or therapeutic discriminative value . This contrasts with many other tumors that now are classified using molecular properties such as microsatellite instability (colon carcinoma), isocitrate dehydrogenase mutation (gliomas), human epidermal growth factor receptor 2 amplification (breast carcinoma) and, most of all, leukemias.
Still, osteosarcoma has been investigated extensively for genetic alterations and numerous mutations have been found . Osteosarcoma shows an unusually high level of chromosomal aberrations, similar to pancreatic carcinoma. But a new class of immune checkpoint inhibitors like nivolumab has scarcely been examined and has shown only a limited effect against osteosarcoma .
Transforming Acidic Coiled-Coil Protein 3 (TACC3) has gained attention since it is associated with esophageal, hepatocellular, gastric carcinoma, and soft-tissue sarcomas. An in-vitro study found a correlation between TACC3 and osteosarcoma cell growth and migration , and now Matsuda and colleagues , in the current study, demonstrate the association of elevated TACC3 immunohistochemical expression with poor prognosis in patients with osteosarcoma. TACC3 expression might not only be a prognostic discriminator, but also a worthwhile target for personalized therapy, since another recent report found a small-molecule TACC3 inhibitor called KHS101 to be effective against breast cancer cells .
Where Do We Need To Go?
Semiquantitative evaluation of TACC3 immunohistochemistry might be distorted by variability of tissue fixation, tumor differentiation, staining procedure, and interpretation. Indeed, in the present study , TACC3 immunohistochemistry did not correlate with TACC3 copy number analysis by polymerase chain reaction (PCR), and fluorescence in-situ hybridization (FISH) analysis was not possible because of tissue alterations from decalcification. Therefore, we do not exactly know what increased TACC3 immunohistochemical staining means. We need to determine whether some osteosarcomas have a TACC3 gene mutation or whether there are irregularities in gene transcription, splice variants, or other mechanisms leading to TACC3 protein accumulation, and if the accumulated structure is normal or a dysfunctional variant of TACC3. Furthermore, it remains unclear whether TACC3 accumulation is a mere consequence of basic pathway alterations or if it is an oncogenic mechanism by itself. We need to find out if TACC3 has predictive value, and a reliable test needs to be established, which then can be adopted by pathologists worldwide.
Aside from TACC3, other mutations and chromosomal alterations in osteosarcoma have shown oncogenic properties in vitro but have not yet been used as predictive markers or drug targets in vivo. Osteosarcoma derives its malignant potential from various pathways, thus giving the tumor escape mechanisms in case one pathway is blocked by an antibody or small molecule . It seems likely that not just a single biologic, but rather a combination of antibodies attacking different pathways, may lead to an improved response.
Considering all these discoveries, it seems important that our next steps must be in the direction of personalized medicine; in particular, we need molecular markers that can inform treatment decisions, and targeted drugs that attack particular properties of each individual patient’s tumor. These approaches could lead to treatment breakthroughs, especially for patients with distant metastases and those who do not respond to classical chemotherapy.
How Do We Get There?
Osteosarcoma is difficult to study because it is relatively uncommon. Most tumors are resected only after chemotherapy, and native tumors are available only from smaller biopsies, which have undergone extensive histopathological workups. Furthermore, most biopsies have been decalcified for histopathological processing, so it is even more difficult to perform reliable molecular examination such as immunohistochemistry, FISH, blotting, or PCR. The tumors show considerable morphologic and genetic heterogeneity, making it even-more difficult to evaluate the molecular properties of the whole tumor from a small biopsy. However, there already are molecular data available from both in-vitro and in-vivo studies, and genome-wide sequencing is becoming more feasible [3, 6, 7].
But creating a coherent picture of the various interacting molecular mechanisms in osteosarcoma emergence and growth remains a challenge. It might be worthwhile to use an in-silico or machine-learning approach to determine how different molecular mechanisms lead into a common final path. Since there already are numerous targeted anticancer drugs available, a better understanding of the molecular mechanisms in osteosarcoma would help researchers choose the most-promising drugs. Pet dogs develop osteosarcoma just like their human counterparts , and animal models better resemble the human disease than do in-vitro studies. Since biologicals are available, seem effective, and have generally tolerable side effects, they may soon be used in canine models. And if effective there, they may be used in patients with osteosarcoma.
Regulatory approval of new drugs for treatment of patients with osteosarcoma should take place in the framework of prospective, and ideally, multicenter studies in order to recruit sufficient numbers of patients, given the rarity of this tumor. These studies should ensure that sufficient amounts of pretreatment tumor tissue are available for extensive molecular testing, and ideally, genome-wide mutation analysis should be performed from each tumor. Genome-wide sequencing is becoming cheaper and faster, and large centers will likely have the facilities and manpower to perform the analyses.
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