Cancer Master Regulators Research Articles

Interaction and Collaboration of SP1, HIF-1, and MYC in Regulating the Expression of Cancer-Related Genes to Further Enhance Anticancer Drug Development.

Specificity protein 1 (SP1), hypoxia-inducible factor 1 (HIF-1), and MYC are important transcription factors (TFs). SP1, a constitutively expressed housekeeping gene, regulates diverse yet distinct biological activities; MYC is a master regulator of all key cellular activities including cell metabolism and proliferation; and HIF-1, whose protein level is rapidly increased when the local tissue oxygen concentration decreases, functions as a mediator of hypoxic signals. Systems analyses of the regulatory networks in cancer have shown that SP1, HIF-1, and MYC belong to a group of TFs that function as master regulators of cancer. Therefore, the contributions of these TFs are crucial to the development of cancer. SP1, HIF-1, and MYC are often overexpressed in tumors, which indicates the importance of their roles in the development of cancer. Thus, proper manipulation of SP1, HIF-1, and MYC by appropriate agents could have a strong negative impact on cancer development. Under these circumstances, these TFs have naturally become major targets for anticancer drug development. Accordingly, there are currently many SP1 or HIF-1 inhibitors available; however, designing efficient MYC inhibitors has been extremely difficult. Studies have shown that SP1, HIF-1, and MYC modulate the expression of each other and collaborate to regulate the expression of numerous genes. In this review, we provide an overview of the interactions and collaborations of SP1, HIF1A, and MYC in the regulation of various cancer-related genes, and their potential implications in the development of anticancer therapy.

P11.82.A TARGETING THE GLIOBLASTOMA MASTER REGULATOR C/EBPß: A PHARMACOKINETIC AND PHARMACODYNAMIC NEOADJUVANT STUDY OF ST101

Abstract BACKGROUND The vast amounts of genomics, epigenomics and transcriptomics data in glioblastoma (GBM) have yet to translate into better outcomes to most patients. One of the main challenges is to how to best integrate these diverse layers of omics to personalize and improve the treatment of glioblastomas. Cancer master regulators are often transcription factors (TFs), which control the expression of many genes and considered promising antitumor targets. CCAAT/enhancer-binding protein β (C/EBPβ) is an abundantly-expressed transcription factor (Zahnow 2009). C/EBPβ was previously described as a master regulator in GBM (Carro 2010). ST101 is a first-in-class cell-penetrating peptide antagonist of C/EBPβ with known ability to cross the blood-brain barrier. We have demonstrated potent anti-tumor activity with ST101 in multiple in vivo models including glioblastoma. Based on early efficacy data on the initial clinical study including objective responses in GBM, we designed this surgical study to further understand the antitumor mechanisms of ST101. METHODS we will recruit total of 12 newly diagnosed GBM and 6 recurrent patients. Recurrent GBM patients who are deemed surgical candidates will be treated with ST101 at the RP2D of 500 mg IV weekly for 2 to 4 weeks and then undergo standard of care surgical resection. After recovery from surgery, patients will continue ST101 until there is significant toxicity or tumor progression. 12 patients with newly diagnosed GBM who had undergone a prior biopsy or partial resection, and that upon further neurosurgical evaluation have an indication for additional debulking surgery will be eligible for this study. Patients will be treated with ST101 at the recommended phase 2 dose for 2 weeks and then undergo standard of care surgical resection. Patients will undergo standard of care treatment with radiation and temozolomide and continue ST101 after recovery from surgery. ST101 plasma concentration will be correlated with ST101 drug levels in enhancing and non-enhancing tumor tissue of recurrent and newly diagnosed patients. We will compare the molecular abnormalities in the post-treatment tissue through deep bulk whole-exome sequencing and mRNAseq against the intra-patient baseline tissue. Pharmacodynamics evaluation will focus on the expression of genes regulated by the transcription factor CEBPβ, such as BCL2, cyclins and cyclin-dependent kinases and inhibition of differentiation genes. Due to the diversity of cell types in the tumor microenvironment and the early data that ST101 can also reprogram M2 macrophages to M1 in addition to its direct antitumor effects, we will perform single nucleus RNAseq on these surgical specimens. Enrollment has started in January 2023 and 6 recurrent and 2 newly diagnosed patients have been accrued.

Crosstalk Between Long Non-coding RNAs, Micro-RNAs and mRNAs: Deciphering Molecular Mechanisms of Master Regulators in Cancer

Cancer is a complex disease, and its study requires deep understanding of several biological processes and their regulation. It is an accepted fact that non-coding RNAs are vital components of the regulation and cross-talk among cancer-related signaling pathways that favor tumor aggressiveness and metastasis, such as neovascularization, angiogenesis, and vasculogenic mimicry. Both long non-coding RNAs (lncRNAs) and micro-RNAs (miRNAs) have been described as master regulators of cancer on their own; yet there is accumulating evidence that, besides regulating mRNA expression through independent mechanisms, these classes of non-coding RNAs interact with each other directly, fine-tuning the effects of their regulation. While still relatively scant, research on the lncRNA-miRNA-mRNA axis regulation is growing at a fast rate, it is only in the last 5 years, that lncRNA-miRNA interactions have been identified in tumor-related vascular processes. In this review, we summarize the current progress of research on the cross-talk between lncRNAs and miRNAs in the regulation of neovascularization, angiogenesis and vasculogenic mimicry.