Liposarcoma: Molecular Genetics and Therapeutics

Sarcomas are a group of heterogeneous tumours with varying genetic basis. Cytogenetic abnormalities range from distinct genomic rearrangements such as pathognomonic translocation events and common chromosomal amplification or loss, to more complex rearrangements involving multiple chromosomes. The different subtypes of liposarcoma are spread across this spectrum and constitute an interesting tumour type for molecular review. This paper will outline molecular pathogenesis of the three main subtypes of liposarcoma: well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic liposarcoma. Both the molecular basis and future avenues for therapeutic intervention will be discussed

The role of MDM2 and CDK4 in well differentiated liposarcoma

© 2015 Dr. Rachel Katherine ConyersTransformation of normal cells to cancer cells is tightly linked to fundamental changes in cell cycle regulation. In addition, oncogenes can aberrantly enhance cell proliferation. Two genes; Cyclin dependent kinase-4 (CDK4) and Murine double minute 2 (MDM2) are amplified and overexpressed in over 90% of well differentiated liposarcomas. Their role in cell cycle control, and regulation of tumour suppressor p53 respectively, strongly suggesting that deregulation of these genes confers some selective advantage to this tumour. To elucidate the role of these genes in the development and progression of liposarcoma I have used transgenic mouse models and in vitro assays. Given the recent development of novel CDK4 inhibitors, I have tested several CDK4 inhibitors (sc-203873, sc-203874, NPCD, PD 0332991) on liposarcoma cell lines (449B, T1000, 778, GOT3) to determine sensitivity to inhibition, cell cycle arrest and downstream effects of inhibition. PD033991 was found to be the most selective and sensitive CDK4 inhibitor and, as such, was used in a siRNA screen of the genome to identify co-modifiers of CDK4 inhibition. A total of 13 genes were identified that produced a resistance phenotype in the context of CDK4 inhibition. Two of these genes; Arrestin, beta 2 (ARRB2) and Dysferlin (DYSF) demonstrated a reproducible resistance phenotype in a series of functional validation studies

Datasheet1_Physician-defined severe toxicities occurring during and after cancer treatment: Modified consensus definitions and clinical applicability in the evaluation of cancer treatment.docx

Overall survival after cancer is increasing for the majority of cancer types, but survivors can be burdened lifelong by treatment-related severe toxicities. Integration of long-term toxicities in treatment evaluation is not least important for children and young adults with cancers with high survival probability. We present modified consensus definitions of 21 previously published physician-defined Severe Toxicities (STs), each reflecting the most serious long-term treatment-related toxicities and representing an unacceptable price for cure. Applying the Severe Toxicity (ST) concept to real-world data required careful adjustments of the original consensus definitions, translating them into standardized endpoints for evaluating treatment-related outcomes to ensure that (1) the STs can be classified uniformly and prospectively across different cohorts, and (2) the ST definitions allow for valid statistical analyses. The current paper presents the resulting modified consensus definitions of the 21 STs proposed to be included in outcome reporting of cancer treatment.</p

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic

Abstract Background Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. Objectives Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. Methods Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. Results Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. Conclusions Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors