TBX3, a member of the ancient and evolutionary conserved T-box transcription factor family, is a critical developmental regulator of several structures including the heart, mammary glands, limbs and lungs. Indeed, mutations in the human TBX3 lead to ulnar mammary syndrome which is characterized by several clinical malformations including hypoplasia of the mammary and apocrine glands, defects of the upper limb, areola, dental structures, heart and genitalia. In contrast, TBX3 has no known function in adult tissues but is frequently overexpressed in a wide range of epithelial and mesenchymal derived cancers. This overexpression greatly impacts several hallmarks of cancer including bypass of senescence, apoptosis and anoikis, promotion of proliferation, tumour formation, angiogenesis, invasion and metastatic capabilities as well as cancer stem cell expansion. The debilitating consequences of having too little or too much TBX3 suggest that its expression levels need to be tightly regulated. While we have a reasonable understanding of the mutations that result in low levels of functional TBX3 during development, very little is known about the factors responsible for the overexpression of TBX3 in cancer. Furthermore, given the plethora of oncogenic processes that TBX3 impacts, it must be regulating several target genes but to date only a few have been identified and characterised. Interestingly, while there is compelling evidence to support oncogenic roles for TBX3, a few studies have indicated that it may also have tumour suppressor functions in certain contexts. Together, the diverse functional elasticity of TBX3 in development and cancer is thought to involve, in part, the protein partners that it interacts with and this area of research has recently received some attention. This review provides an insight into the significance of TBX3 in development and cancer and identifies research gaps that need to be explored to shed more light on this transcription factor.

Sarcomas are a heterogeneous group of neoplasms of mesenchymal origin. Approximately 80% arise from soft tissue and 20% originate from bone. To date more than 100 sarcoma subtypes have been identified and they vary in molecular characteristics, pathology, clinical presentation and response to treatment. While sarcomas represent <1% of adult cancers, they account for approximately 21% of paediatric malignancies and thus pose some of the greatest risks of mortality and morbidity in children and young adults. Metastases occur in one-third of all patients and approximately 10–20% of sarcomas recur locally. Surgery in combination with preoperative and postoperative therapies is the primary treatment for localized sarcoma tumours and is the most promising curative possibility. Metastasized sarcomas, on the other hand, are treated primarily with single-agent or combination chemotherapy, but this rarely leads to a complete and robust response and often becomes a palliative form of treatment. The heterogeneity of sarcomas results in variable responses to current generalized treatment strategies. In light of this and the lack of curative strategies for metastatic and unresectable sarcomas, there is a need for novel subtype-specific treatment strategies. With the more recent understanding of the molecular mechanisms underlying the pathogenesis of some of these tumours, the treatment of sarcoma subtypes with targeted therapies is a rapidly evolving field. This review discusses the current management of sarcomas as well as promising new therapies that are currently underway in clinical trials.

Rhabdomyosarcoma (RMS) forms in skeletal muscle and is the most common soft tissue sarcoma in children and adolescents. Current treatment is associated with debilitating side effects and treatment outcomes for patients with metastatic disease are dismal. Recently, a novel binuclear palladacycle, AJ-5, was shown to exert potent cytotoxicity in melanoma and breast cancer and to present with negligible adverse effects in mice. This study investigates the anti-cancer activity of AJ-5 in alveolar and embryonal RMS. IC50 values of ≤ 0.2 µM were determined for AJ-5 and it displayed a favourable selectivity index of >2. Clonogenic and migration assays showed that AJ-5 inhibited the ability of RMS cells to survive and migrate, respectively. Western blotting revealed that AJ-5 induced levels of key DNA damage response proteins (γH2AX, p-ATM and p-Chk2) and the p38/MAPK stress pathway. This correlated with an upregulation of p21 and a G1 cell cycle arrest. Annexin V-FITC/propidium iodide staining revealed that AJ-5 induced apoptosis and necrosis. Apoptosis was confirmed by the detection of cleaved PARP and increased levels and activity of cleaved caspases-3, -7, -8 and -9. Furthermore, AJ-5 reduced autophagic flux as shown by reduced LC3II accumulation in the presence of bafilomycin A1 and a significant reduction in autophagosome flux J. Finally, pharmacokinetic studies in mice show that AJ-5 has a promising half-life and that its volume of distribution is high, its clearance low and its intraperitoneal absorption is good. Together these findings suggest that AJ-5 may be an effective chemotherapeutic with a desirable mechanism of action for treating drug-resistant and advanced sarcomas.

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Cisplatin and second-generation alternatives to cisplatin, represent some of the most active and clinically useful agents in the treatment of cancer. However, their application in the clinic is marred by side-effects and drug resistance. We have identified the binuclear palladacycle, AJ-5, as a lead anticancer compound with potent activity against advanced melanomas and estrogen receptor -positive and -negative breast cancers. AJ-5 displayed an IC50 of 0.2μM in melanoma and breast cancer cell lines which was 50 fold less than that for cisplatin and our in vivo results show that it efficiently reduces melanomas in nude mice without any obvious side effects. AJ-5 also showed activity against breast cancer stem cells which are associated with drug-resistance and often not targeted by traditional chemotherapeutic agents. This study investigates the potential of AJ-5 as an anti-cancer agent in sarcomas, which are a heterogeneous group of neoplasms that account for approximately 21% of paediatric malignancies and treatment outcomes for patients with metastatic disease are dismal. Cytotoxicity assays were performed and sub-micromolar IC50 concentrations were obtained for rhabdomyosarcoma, chondrosarcoma, liposarcoma, synovial sarcoma and osteosarcoma. Clonogenic assays show that AJ-5 greatly compromises the long-term ability of the sarcoma cells to survive and proliferate. To determine the underlying molecular mechanisms by which AJ-5 exerts its cytotoxicity, western blot analyses were performed with antibodies to key proteins involved in the DNA damage response in rhabdomyosarcoma cell lines. The results show that AJ-5 induces high levels of γH2AX, a marker of double-stranded DNA breaks, and that it may exert it's cytotoxicity through the p38 MAP kinase stress pathway. Furthermore, Annexin VFITC/propidium iodide staining, Caspase Glo assays and western blotting demonstrated that AJ-5 induce intrinsic and extrinsic apoptosis more effectively than doxorubicin, a drug currently used in the treatment of rhabdomyosarcomas. AJ-5 treatment also led to autophagy as confirmed by the formation of autophagosomes, increased levels of LC3-II and the presence of LC3 puncta. Finally, pharmacokinetic studies show that AJ-5 has a promising half-life of 11.2 hours in mice and in addition its volume of distribution is high and its clearance is low while its intraperitoneal absorption is good. Thus the PK data correlates well with our observed efficacy of the drug in our mouse model. Together these findings suggest that AJ-5 may be an effective chemotherapeutic for treating a range of drug-resistant and advanced cancers. Citation Format: Jenna Bleloch, Reyna Ballim, Angelique Blanckenberg, Selwyn Mapolie, Serah Kimani, Sharon Prince. A novel palladacycle complex with anti-cancer activity against breast cancer and melanomas also exhibits potent cytotoxicity in a range of sarcomas [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B38.