Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts

Key Points HERC4 is the first identified ubiquitin ligase that mediates c-Maf ubiquitination and degradation. HERC4 suppresses MM cell proliferation and delays MM tumor growth.

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Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽

10.1182/blood-2019-126298 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1844-1844

Author(s):

John Richards ◽

Myriam N Bouchlaka ◽

Robyn J Puro ◽

Ben J Capoccia ◽

Ronald R Hiebsch ◽

...

Keyword(s):

Multiple Myeloma ◽

Combination Therapy ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Cells ◽

Tumor Growth Inhibition ◽

Employment Equity ◽

Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

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TLR4 signaling drives mesenchymal stromal cells commitment to promote tumor microenvironment transformation in multiple myeloma

Cell Death and Disease ◽

10.1038/s41419-019-1959-5 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 7

Author(s):

Cesarina Giallongo ◽

Daniele Tibullo ◽

Giuseppina Camiolo ◽

Nunziatina L. Parrinello ◽

Alessandra Romano ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Cancer Progression ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Immune Escape ◽

In Vivo Model ◽

Th2 Response ◽

Tlr4 Signaling

Abstract Inflammation represents a key feature and hallmark of tumor microenvironment playing a major role in the interaction with mesenchymal stromal cells (MSC) in cancer progression. The aim of the present study was to investigate the crosstalk between MSCs and myeloma cells (MM) in the pro-inflammatory microenvironment promoting immune evasion and tumor growth. MSC were collected from patients with diagnosis of MGUS (n = 10), smoldering myeloma (n = 7), multiple myeloma at diagnosis (n = 16), relapse (n = 5) or refractory (n = 3), and from age-matched healthy controls (HC, n = 10) and cultured with peripheral blood mononucleated cells (PBMC) from healthy volunteer donors. Similarly to MM, we showed that MSC from smoldering multiple myeloma (SMM) patients activated neutrophils and conferred an immunosuppressive and pro-angiogenic phenotype. Furthermore, co-cultures of plasma cells (PC) and HC-MSC suggested that such activation is driven by MM cells through the switching into a pro-inflammatory phenotype mediated by toll-like receptor 4 (TLR4). These results were further confirmed using a zebrafish as an immunocompetent in vivo model, showing the role of MM–MSC in supporting PCs engraftment and Th2 response. Such effect was abolished following inhibition of TLR4 signaling in MM–MSC before co-injection with PC. Moreover, the addition of a TLR4 inhibitor in the co-culture of HC-MSC with MM cells prevented the activation of the pro-tumor activity in PC-educated MSC. In conclusion, our study provides evidence that TLR4 signaling plays a key role in MSC transformation by inducing a pro-tumor phenotype associated with a permissive microenvironment allowing immune escape and tumor growth.

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Sustained Expression of Early Growth Response Protein-1 Blocks Angiogenesis and Tumor Growth

Cancer Research ◽

10.1158/0008-5472.can-05-2732 ◽

2006 ◽

Vol 66 (13) ◽

pp. 6708-6713 ◽

Cited By ~ 49

Author(s):

Markus Lucerna ◽

Jiri Pomyje ◽

Diana Mechtcheriakova ◽

Alexandra Kadl ◽

Florian Gruber ◽

...

Keyword(s):

Tumor Growth ◽

Growth Response ◽

Early Growth ◽

Early Growth Response

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PGC 1β regulates multiple myeloma tumor growth through LDHA ‐mediated glycolytic metabolism

Molecular Oncology ◽

10.1002/1878-0261.12363 ◽

2018 ◽

Vol 12 (9) ◽

pp. 1579-1595 ◽

Cited By ~ 9

Author(s):

Hongyu Zhang ◽

Ling Li ◽

Qi Chen ◽

Min Li ◽

Jia Feng ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Growth ◽

Glycolytic Metabolism

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Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

International Journal of Molecular Sciences ◽

10.3390/ijms21207539 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7539

Author(s):

Amro M. Soliman ◽

Teoh Seong Lin ◽

Pasuk Mahakkanukrauh ◽

Srijit Das

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Tumor Growth ◽

Malignant Transformation ◽

Bone Disease ◽

Clinical Management ◽

Potential Role ◽

Plasma Cells ◽

The Usa

Multiple myeloma (MM) is a cancerous bone disease characterized by malignant transformation of plasma cells in the bone marrow. MM is considered to be the second most common blood malignancy, with 20,000 new cases reported every year in the USA. Extensive research is currently enduring to validate diagnostic and therapeutic means to manage MM. microRNAs (miRNAs) were shown to be dysregulated in MM cases and to have a potential role in either progression or suppression of MM. Therefore, researchers investigated miRNAs levels in MM plasma cells and created tools to test their impact on tumor growth. In the present review, we discuss the most recently discovered miRNAs and their regulation in MM. Furthermore, we emphasized utilizing miRNAs as potential targets in the diagnosis, prognosis and treatment of MM, which can be useful for future clinical management.

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Biallelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells

Cancer Science ◽

10.1111/cas.14386 ◽

2020 ◽

Vol 111 (5) ◽

pp. 1663-1675 ◽

Cited By ~ 1

Author(s):

Jo Kanasugi ◽

Ichiro Hanamura ◽

Akinobu Ota ◽

Sivasundaram Karnan ◽

Vu Quang Lam ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Growth ◽

Akt Signaling ◽

Myeloma Cells

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Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models

Cancers ◽

10.3390/cancers12123857 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3857

Author(s):

Zhanfang Guo ◽

Tina Primeau ◽

Jingqin Luo ◽

Cynthia Zhang ◽

Hua Sun ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Triple Negative Breast Cancer ◽

Growth Response ◽

Triple Negative ◽

Pi3k Pathway ◽

Pi3k Inhibitor ◽

Pi3k Inhibitors ◽

Patient Derived Xenograft ◽

Phosphorylated Akt

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.

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Patient-specific simulation of tumor growth, response to the treatment, and relapse of a lung metastasis: a clinical case

Journal of Computational Surgery ◽

10.1186/s40244-014-0014-1 ◽

2015 ◽

Vol 2 (1) ◽

Cited By ~ 2

Author(s):

Thierry Colin ◽

François Cornelis ◽

Julien Jouganous ◽

Jean Palussière ◽

Olivier Saut

Keyword(s):

Tumor Growth ◽

Lung Metastasis ◽

Growth Response ◽

Clinical Case ◽

Patient Specific

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A Novel In Vivo Animal Model for Human Multiple Myeloma Based on Bioluminescence Imaging of Tumor Cell Growth.

Blood ◽

10.1182/blood.v106.11.3452.3452 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3452-3452

Author(s):

Anton C. Martens ◽

Henk Rozemuller ◽

Ellen van der Spek ◽

Lijnie Bogers-Boer ◽

Niels van de Donk ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Tumor Growth ◽

Quantitative Evaluation ◽

Bioluminescence Imaging ◽

Growth Curves ◽

Population Doubling ◽

Tumor Mass ◽

In Vivo Animal Model

Abstract Preclinical testing of new therapeutical strategies for the treatment of multiple myeloma (MM) requires animal models that closely resemble human disease and allow quantitative evaluation of the applied therapy. Models that meet both requirements have thus far not been described. Here we present a novel in vivo MM model by engraftment of MM U266 or RPMI-8226/S cells, both of human origin, into RAG2γc double knock-out mice. These mice are totally immune deficient because they lack T-, B and NK cells and the mice easily accept human cells (van Rijn et al., Blood 2003, Rozemuller et al., 2004). After intravenous injection of 2x106 MM cells engraftment and outgrowth occurred in all mice but was limited to the bone marrow compartment only. Flow cytometry (FCM) confirmed the presence of human CD45/38/138 positive MM cells in femur, spine, tibia and sternum bone specimens. Infiltration into other organs was not observed. In a next step MM cells were stably transduced using a retroviral vector encoding both the Green Fluorescent Protein (GFP) and firefly Luciferase (fLuc) marker genes. Technical advances in recent years in optical imaging by Bioluminescence Imaging (BLI) techniques allow visualization and quantification of bioluminescent light by detecting photons that are transmitted through mammalian tissue. When luciferase converts the substrate luciferin, photons are emitted that can be registered by using sensitive CCCD cameras. The absolute number of photons that are produced correlates, in our application, with local tumor mass. Mice were injected i.v. with 2x106 GFP-fLuc transduced MM cells (U266 or RPMI8226/S) and imaged weekly using BLI. Within 2 weeks after injection significant BLI signals were detectable. Per mouse 5-10 foci showed luciferase activity, predominantly in the pelvic region, skull, limbs, sternum, ribs and the spine. This low frequency of engraftment is in line with earlier reports on RPMI8226/S (Mitsiades et al., Cancer Res 2003). At 9 weeks the first mice developed hind leg paralysis which could be attributed to tumor associated spinal lesions. After 12 weeks the last mouse was sacrificed. BLI revealed that the intensity of light production at the various sites of tumor growth within individual mice as well as between mice showed a similar increase. This reflects an increase in tumor mass. Quantitative analysis of subsequent BLI images allowed construction of tumor growth curves of the total tumor mass per mouse as well as for the individual foci of MM growth in individual mice. We typically observed exponential growth, with growth curves running parallel with an average population doubling time of approximately 4–5 days. The range in which tumor growth could be monitored (and as a consequence also the response to treatment) spans 3–4 decades. In contrast with previously reported murine models for human MM where -next to bone marrow homing- also extra-skeletal tumors were observed our model almost exclusively shows homing of MM cells to the BM and is therefore more consistent with the clinical manifestation in myeloma patients. The major advantage of the model is the option for quantitative evaluation of the effect of a given treatment on the tumorload. Currently we are studying the efficacy of newly developed geranyl-geranyl-transferase inhibitors (GGTI). In conclusion, we have developed a novel in vivo model to study the characteristics of homing and outgrowth of MM and for quantitative evaluation of the efficacy of the therapeutic intervention applied.

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