Therapeutics For Metastasis Research Articles

Abstract 2973: Rac inhibitors for cancer therapy

Abstract Among all cancers worldwide, breast cancer is the first cause of death in women. One of the most aggressive subtypes of breast cancer is the triple negative form, which account for the 10-15% of breast cancer cases. Due to its complex heterogeneity triple negative breast cancer available treatments are limited, being chemotherapy in the first line of use. Despite advances in the search for new treatments, there is still a lack of effective therapies, being the metastatic disease the principal cause of breast cancer mortality. Therefore, it is critical to develop a new and effective strategies to inhibit metastasis. The Rho GTPase Rac has been identified as a promising target for anti-metastatic cancer therapy as it has been shown to play key roles in metastatic cancer cells dynamics as: cellular adhesion, migration, proliferation, survival and invasion. To this extent, in an effort to find a compound with increased Rac inhibitory capacity our group developed Ehop-016 derivatives HV-107 and HV-118. Previously we have reported HV-107 and HV-118 to affect cell viability promoting a G2-M cell cycle arrest with a sub-G1 population indicative of cell death in MDA-MB-231. Also, an increase of caspases activity validating apoptosis as a mechanism of cell death was shown. In addition, a decrease in tumor growth and metastasis by ~35 to 40% in an in vivo study using HV-118 at 1 mg/kg body weightwas also reported. Currently, through pulldown assays we have showed HV-107 and HV-118 to inhibit Rac activity at~500-2000 nM and 10 nM respectively in MDA-MB-231 and MDA-MB-468 breast cancer cells. Using trypan blue excision assay HV-107(>500 nM) and HV-118(>50 nM) were shown to affect cell viability promoting a G2-M cell cycle arrest in MDA-MB-468. We also demonstrated HV-107 and HV-118 to inhibit the direct downstream effector of Rac, PAK at >500 nM(HV-107) and >50 nM(HV-118) in MDA-MB-231 cells. In addition, HV-107 was also shown to increase Rho activity at concentrations significantly higher than the effective for Rac inhibition. Rho activity up-regulation has been reported to negatively affect migration of cancerous cells. Finally, we tested HV-107 in a mouse model of metastatic breast cancer. A decrease of ~ 40% in liver metastasis was shown for mice treated with 5 mg/kg BW HV-107. Taken together, our results indicate HV-107 and HV-118 are approximately 4-100 times more efficient than the parent compound Ehop-016 and have potential as anti-breast cancer metastasis therapeutics. This study is supported by NIH Grant 1SC1GM122691, and PRINBRE P20GM103475 from NIGMS of the NIH to GVC Citation Format: Grace Enid Velez Crespo, Eliud Hernandez, Suranganie Dharmawardhane, Cornelis Vlaar, Linnette Castillo, Lilia Kucheryavykh. Rac inhibitors for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2973.

Tolerance of cancer cells against amino acids deprivation in tumour microenvironments

New approaches for treating cancers are required and advances in 'omics' technologies including genomics, epigenomics, transcriptomics could provide valuable treatment options. Associate Professor Tsuyoshi Osawa, Research Center for Advanced Science and Technology (RCAST), University of Tokyo, believes that integrative techniques are essential in combating cancer. Osawa's lab is utilising a pioneering approach called nutriomics that involves applying multiple omics technologies to cancer biology. These omics approaches can be used to generate detailed genetic and molecular profiles of whole tumours, allowing researchers to discover important information about the tumour cells. In addition, they provide an opportunity to explore the healthy cells surrounding the tumour, thereby establishing a picture of the interactions between the tumour and the microenvironment in which it exists, which is important information that could be exploited for treatments methods. Using the omics approach, the researchers have been able to identify and describe the functions of the metabolites contributing to the malignant progression of cancer cells. They found that hypoxia, nutrient starvation and acidic pH all induce tumour aggressiveness by epigenetic regulation. Osawa and the team now want to identify further cancer metabolites that lead to malignancy and, ultimately, develop therapeutics for metastasis and recurrent advanced cancer from the viewpoint of an integrative multiomics approach.

Invasion and Metastasis as a Central Hallmark of Breast Cancer.

Hanahan and Weinberg introduced the “hallmarks of cancer” and typified essential biological abilities acquired by human cancer. Since then, a growing understanding of hallmark principles associated with breast cancer has assisted knowledge-based therapeutics development; however, despite the rapidly increasing number of targeted therapeutics, enduring disease-free responses for most forms of breast cancer is rare. Invasion and metastasis are the most defining feature of breast cancer malignancy and the leading cause of patient mortality. Hence, we propose a modified hallmarks model adapted to breast cancer, in which invasion and metastasis are shifted to the center of attention, thereby emphasizing it as a potentially superior therapeutic target. Although the scientific community highly appreciates the importance of the invasion and metastasis hallmark, as can be demonstrated by the growing number of publications on breast cancer metastasis, very few clinical trials concentrate on testing anti-metastasis inhibitors and even fewer trials focus on inhibitors for breast cancer metastasis. Here, we discuss the obstacles of applying research on invasion and metastasis therapeutics into the clinic and present current developments that could provide a potential solution to this dilemma.

Abstract A57: Characterization of novel regulators of epithelial-mesenchymal transition in human cancer cells

Abstract The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by cancer cells of several cancer types. Recently, a few kinases, such as FYN and c-Met, were reported to participate in regulating EMT. However, the roles of the majority of >700 human kinases in EMT and cancer progression are still unknown. Here we carried out human kinase cDNA screens to identify novel regulators of EMT. Many unknown EMT regulators and a few known ones such as PI3K, PDGFRA, FYN and c-Met, were found to up-regulate mesenchymal marker vimentin. Some also increase expression of fibronectin and N-cadherin, as well as EMT transcriptional regulators, such as ZEB1/2, Snail and Slug. At the same time, the cells acquired mesenchymal phenotypes, such as increased migration/invasion activity, enhanced capability to survive and proliferate in growth factor deprivation condition or under drug treatments. Interestingly, FACS analysis also showed a substantial increase in CD44hiCD24low population in kinase-transducted mammary gland epithelial cells. The increase of CD44hi population could be attributed to increase of a CD44 mesenchymal variant — the standard form CD44s and decrease of the epithelial variant CD44 v8-10. And this alternation was associated with down-regulation of ESRP1 and ESRP2, two splicing factors that regulate CD44 splicing and EMT. Furthermore, the mammary gland epithelial cells undergoing EMT showed increase capability of forming mammosphere and differentiating into other lineage, such as osteoblast and adipocyte. Importantly, some of these novel EMT regulators are associated with tumor progression and stemness of human cancers. Further study of these novel EMT regulators promises to provide new mechanisms of cancer progression, and may also lead to development of new prognostic markers and therapeutics for metastasis. Citation Format: Linna Li, Nanping Ai, Mohit Hulsurkar, Wenliang Li. Characterization of novel regulators of epithelial-mesenchymal transition in human cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A57.

Different Spontaneous Pulmonary Metastasis Inhibitions against Lewis Lung Carcinoma in Mice by Bisdioxopiperazine Compounds of Different Treatment Schedules

Spontaneous neoplasm metastasis, a fatalist pathological feature of cancer, is a long-evolving, multi-steps process that can now only be treated or controlled by drugs or immuno-modulators. As we have previously hypothesized, each drug or immuno-modulator might act differently within various stages of a metastasis. Therefore any researches helping to determine these differences will be beneficial for updating therapeutics for metastasis. In this work, we have testified this hypothesis by using a series of well-known anti-metastatic agents – Bisdioxopiperazine compounds.

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

Identifying versatile inhibitors of metastasis that operate in multiple sites against distinct cancer cell types is important for designing novel therapeutics for metastasis. We show that multiple tissues of timp-3-/- mice are more susceptible to metastatic colonization. Overall, a 5-14-fold increase in liver and kidney colonization occurred by EL-4 lymphoma cells, and a twofold increase upon targeting B16F10 melanoma cells to the bone or lung of timp-3-/- mice. There was a general lack of macrophage or neutrophil localization to metastases in the liver, kidney and lung, and of osteoclasts to bone in both genotypes. Analysis of lung showed that proliferation or angiogenesis were unaltered within the metastatic colonies. Lung-trap assays revealed that initial tumor cell trapping was similar in the lung vasculature of timp-3-/- and wild-type mice. However, more tumor cells were found in timp-3-/- lungs at 48 and 96 h after tumor cell injection indicating more efficient extravasation and initial proliferation. Activation of pro-MMP-2 was greater in timp-3-/- lungs at these time points. These data demonstrate TIMP-3 functions to inhibit metastatic dissemination of diverse cancer cells to multiple organs. TIMP-3 regulates MMP-2 activation to limit tumor cell extravasation and subsequent colonization of the lung, without augmenting inflammatory cell response.