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Aberrant pregnancy-associated plasma protein-A expression in breast cancers prognosticates clinical outcomes

- Prithviraj, Prashanth, Anaka, Matthew, Thompson, Erik, Sharma, Revati, Walkiewicz, Marzena, Tutuka, Candani, Behren, Andreas, Kannourakis, George, Jayachandran, Aparna

  • Authors: Prithviraj, Prashanth , Anaka, Matthew , Thompson, Erik , Sharma, Revati , Walkiewicz, Marzena , Tutuka, Candani , Behren, Andreas , Kannourakis, George , Jayachandran, Aparna
  • Date: 2020
  • Type: Text , Journal article
  • Relation: Scientific Reports Vol. 10, no. 1 (2020), p.
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  • Description: Elevated levels of pregnancy-associated plasma protein-A (PAPP-A) have been implicated in the pathogenesis of various malignancies, including breast cancers. Breast cancer is one of the most frequent carcinomas and is the second most common cancer type detected in women of child-bearing age. Throughout pregnancy PAPP-A is produced and secreted by the placental syncytiotrophoblast cells; co-incidentally pregnancy-associated breast cancers often have an aggressive clinical course. The components of the PAPP-A/IGF axis was assessed in a panel of breast cancer cell lines. Using neutralising antibodies the impact of PAPP-A/IGF axis on cell motility was evaluated. PAPP-A was expressed in four of the twelve breast cancer cell lines tested. Blocking PAPP-A and IGFBP4 with neutralising antibodies significantly decreased motiliy of MDA-MB-231 cells. Upregulation of PAPP-A expression in breast tumours resulted in a trend towards worse overall survival. Notably, PAPP-A expression also positively correlated with epithelial-to-mesenchymal transition markers. In conclusion, these results indicate that PAPP-A plays an important role in breast cancer progression and it may be a promising therapeutic target in breast cancer. © 2020, The Author(s).

Combined inhibition of TGF-beta 1-induced EMT and PD-L1 silencing re-sensitizes hepatocellular carcinoma to sorafenib treatment

- Shrestha, Ritu, Prithviraj, Prashanth, Bridle, Kim, Crawford, Darrell, Jayachandran, Aparna

Prognostic role of immune checkpoint regulators in cholangiocarcinoma : a pilot study

- Cao, Lu, Prithviraj, Prashanth, Shrestha, Ritu, Sharma, Revati, Kannourakis, George

  • Authors: Cao, Lu , Prithviraj, Prashanth , Shrestha, Ritu , Sharma, Revati , Kannourakis, George
  • Date: 2021
  • Type: Text , Journal article
  • Relation: Journal of Clinical Medicine Vol. 10, no. 10 (2021), p.
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  • Description: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy associated with steadily increasing incidence and poor prognosis. Ongoing clinical trials are assessing the effectiveness and safety of a few immune checkpoint inhibitors (ICIs) in CCA patients. However, these ICI treatments as monotherapies may be effective for a proportion of patients with CCA. The prevalence and distribution of other immune checkpoints (ICs) in CCA remain unclear. In this pilot study, we screened databases of CCA patients for the expression of 19 ICs and assessed the prognostic significance of these ICs in CCA patients. Notably, expression of immune modulator IDO1 and PD-L1 were linked with poor overall survival, while FASLG and NT5E were related to both worse overall survival and progression-free survival. We also identified immune modulators IDO1, FASLG, CD80, HAVCR2, NT5E, CTLA-4, LGALS9, VTCN1 and TNFRSF14 that synergized with PD-L1 and correlated with worse patient outcomes. In vitro studies revealed that the expression of ICs was closely linked with aggressive CCA subpopulations, such as cancer stem cells and cells undergoing TGF-β and TNF-α-mediated epithelial-to-mesenchymal transition. These findings suggest that the aforementioned IC molecules may serve as potential prognostic biomarkers and drug targets in CCA patients, leading to lasting and durable treatment outcomes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Prashanth Prithviraj, Revati Sharma, George Kannourakis” is provided in this record**

Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma

- Sharma, Revati, Kadife, Elif, Myers, Mark, Kannourakis, George, Prithviraj, Prashanth, Ahmed, Nuzhat

  • Authors: Sharma, Revati , Kadife, Elif , Myers, Mark , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
  • Date: 2021
  • Type: Text , Journal article , Review
  • Relation: Journal of Experimental and Clinical Cancer Research Vol. 40, no. 1 (2021), p.
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  • Description: Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies. © 2021, The Author(s).

Precision medicine : an optimal approach to patient care in renal cell carcinoma

- Sharma, Revati, Kannourakis, George, Prithviraj, Prashanth, Ahmed, Nuzhat

  • Authors: Sharma, Revati , Kannourakis, George , Prithviraj, Prashanth , Ahmed, Nuzhat
  • Date: 2022
  • Type: Text , Journal article , Review
  • Relation: Frontiers in Medicine Vol. 9, no. (2022), p.
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  • Description: Renal cell cancer (RCC) is a heterogeneous tumor that shows both intra- and inter-heterogeneity. Heterogeneity is displayed not only in different patients but also among RCC cells in the same tumor, which makes treatment difficult because of varying degrees of responses generated in RCC heterogeneous tumor cells even with targeted treatment. In that context, precision medicine (PM), in terms of individualized treatment catered for a specific patient or groups of patients, can shift the paradigm of treatment in the clinical management of RCC. Recent progress in the biochemical, molecular, and histological characteristics of RCC has thrown light on many deregulated pathways involved in the pathogenesis of RCC. As PM-based therapies are rapidly evolving and few are already in current clinical practice in oncology, one can expect that PM will expand its way toward the robust treatment of patients with RCC. This article provides a comprehensive background on recent strategies and breakthroughs of PM in oncology and provides an overview of the potential applicability of PM in RCC. The article also highlights the drawbacks of PM and provides a holistic approach that goes beyond the involvement of clinicians and encompasses appropriate legislative and administrative care imparted by the healthcare system and insurance providers. It is anticipated that combined efforts from all sectors involved will make PM accessible to RCC and other patients with cancer, making a tremendous positive leap on individualized treatment strategies. This will subsequently enhance the quality of life of patients. Copyright © 2022 Sharma, Kannourakis, Prithviraj and Ahmed.
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