Prostate cancer (PC) is among the most commonly diagnosed malignancies and the second leading cause of cancer-related deaths in men. Although significant progress in the development of early detection tests has led to improved management of patients diagnosed with organ-confined PCs, the progression to locally invasive and metastatic hormone-refractory PCs (HRPCs) typically leads to treatment resistance, disease relapse and the death of patients. Therefore, a better understanding of etiological causes responsible for PC initiation and progression and treatment resistance is needed to identify novel molecular therapeutic targets. Recent lines of evidence have revealed that the malignant transformation of adult prostatic stem/progenitor cells into highly tumorigenic PC-initiating cells may provide critical functions in PC progression, metastases at distant tissues, treatment resistance and disease relapse. In considering these advances, the central hypothesis of this proposal is that the activation of specific oncogenic products induced in PC-initiating cells and their progenies during PC etiology and progression, including an up-regulation of EGFR and hedgehog signaling elements, may cooperate for their sustained growth, survival, invasion, metastases, treatment resistance and disease relapse. Based on this hypothesis, the long-term objective is to evaluate the potential benefit to simultaneously target EGFR and hedgehog cascades for eradicating PC- and metastasis-initiating cells and their progenies and improving the current clinical anti-androgenic treatments and docetaxel-based chemotherapies against locally invasive, androgen independent and metastatic PCs. For this, we will use in vitro and in vivo human PC cell models, and a large panel of patient's prostatic tissues relevant to prostate carcinogenesis.
Three specific aims are proposed.
AIM I will establish the specific functions and molecular mechanisms of EGFR and hedgehog pathways in the malignant transformation of PC stem/progenitor cells and their progenies during PC initiation and progression.
AIM II will identify the drug resistance-associated molecules modulated through the activation of EGF-EGFR and sonic hedgehog cascades in PC stem/progenitor cells versus their progenies.
AIM III will establish the therapeutic benefit of co-targeting EGFR and sonic hedgehog pathways for eradicating PC- and metastasis-initiating cells and their progenies and improving current clinical therapies. Altogether, these studies should delineate the specific functions provided by EGFR and hedgehog pathways in the acquisition of a more malignant phenotype and resistance of PC stem/progenitor cells and their progenies to current clinical therapies. The therapeutic interest of co-targeting EGFR and hedgehog cascades to eradicate the total PC cell mass and improve current anti-androgenic treatments and docetaxel-based chemotherapies for treating PC patients and thereby prevent disease relapse and the death of patients will be established.
Description of research program The research program aims to establish the implications of EGFR and hedgehog cascades and other interacting pathways in the malignant transformation of PC stem/progenitor cells and their progenies and treatment resistance and validate novel therapeutic targets for improving current therapies and preventing disease relapse and the death of PC patients. The studies will consist to delineate the gene products modulated through the EGFR and hedgehog pathways that can cooperate in PC progression and treatment resistance and validate novel therapeutic targets for eradicating total PC cell mass by using human PC cell models and prostatic tissue specimens from patients relevant to prostate carcinogenesis.
|Dutta, Samikshan; Roy, Sohini; Polavaram, Navatha S et al. (2016) NRP2 transcriptionally regulates its downstream effector WDFY1. Sci Rep 6:23588|
|Mimeault, Murielle; Rachagani, Satyanarayana; Muniyan, Sakthivel et al. (2015) Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer. Oncotarget 6:3887-903|
|Muniyan, Sakthivel; Chen, Siu-Ju; Lin, Fen-Fen et al. (2015) ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells. Cell Signal 27:2261-71|
|Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel et al. (2015) Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells. PLoS One 10:e0131811|
|Joshi, Suhasini; Kumar, Sushil; Choudhury, Amit et al. (2014) Altered Mucins (MUC) trafficking in benign and malignant conditions. Oncotarget 5:7272-84|
|Mimeault, Murielle; Batra, Surinder K (2014) Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers. Cancer Epidemiol Biomarkers Prev 23:234-54|
|Mimeault, Murielle; Batra, Surinder K (2014) Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies. Mol Aspects Med 39:3-32|
|Muniyan, Sakthivel; Ingersoll, Matthew A; Batra, Surinder K et al. (2014) Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor. Biochim Biophys Acta 1846:88-98|
|Kaur, Sukhwinder; Momi, Navneet; Chakraborty, Subhankar et al. (2014) Altered expression of transmembrane mucins, MUC1 and MUC4, in bladder cancer: pathological implications in diagnosis. PLoS One 9:e92742|
|Seshacharyulu, Parthasarathy; Pandey, Poomy; Datta, Kaustubh et al. (2013) Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett 335:9-18|
Showing the most recent 10 out of 32 publications