High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.</p

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2, and RAG2x γc mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2x γc mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting

Chronic Viral Infection and Primary Central Nervous System Malignancy

Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies

The Role of IL-17D in Immunosurveillance

The pathology of malignancy and viral infection force cells into the "stressed state," characterized by altered metabolism and imbalanced reactive oxidative species (ROS) ¹⁻³. This generalized state of cellular stress engenders a protective surveillance response by the host immune system⁴⁻¹¹. Under homeostatic conditions, the immune surveillance of stressed cells leads to their destruction; and, thus, many stressed cells experience tremendous selective pressure to develop immune-evasive programs⁵⁻⁸, ¹². Targeting these immune evasive programs in stressed cells as well as identifying the signaling pathways and molecules that influence surveillance have been a top priority¹³⁻¹⁵. We hypothesize that stressed cell-expressed factors can influence the nature and activity of immune cells, thereby determining whether tumors and viral infections progress. To address this central hypothesis, we have endeavored to: First, define how the immune system influences tumor development and progression; Second, explore which signals can recruit immune cells into tumors; and, Third, to determine how cellular stress inherent to malignancy or viral infection induce immune- cell recruiting signals to initiate immunosurveillanc

HER2 and HER3 as Therapeutic Targets in Head and Neck Cancer.

Work over the past several decades has identified that aberrations in the ErbB signaling pathways are key drivers of oncogenesis, and concurrent efforts to discover targetable vulnerabilities to counter this aberrant oncogenic signaling offer tremendous promise in treating a host of human cancers. These efforts have been centered primarily on EGFR (also known as HER1), leading to the discovery of the first targeted therapies approved for head and neck cancer. More recently, HER2 and HER3 signaling pathways have been identified as highly dysregulated in head and neck cancer. This review highlights the HER2 and HER3 signaling pathways and clinical efforts to target these receptors and their aberrant signaling to treat head and neck squamous cell carcinomas and other head and neck malignancies, including salivary gland carcinomas. This includes the use of small molecule inhibitors and blocking antibodies, both as single agents or as part of multimodal precision targeted and immunotherapies

Defining the Role of Immunotherapy in the Curative Treatment of Locoregionally Advanced Head and Neck Cancer: Promises, Challenges, and Opportunities.

Recent advancements in the development of immunotherapies have raised the hope for patients with locally-advanced HNSCC (LA-HNSCC) to achieve improved oncologic outcomes without the heavy burden of treatment-related morbidity. While there are several ongoing late phase clinical trials that seek to determine whether immunotherapy can be effectively employed in the definitive setting, initial results from concurrent immuno-radiotherapy therapy trials have not shown strong evidence of benefit. Encouragingly, evidence from preclinical studies and early-phase neoadjuvant studies have begun to show potential pathways forward, with therapeutic combinations and sequences that intentionally spare tumor draining lymphatics in order to maximize the synergy between definitive local therapy and immunotherapy. The intent of this review is to summarize the scientific rationale and current clinical evidence for employing immunotherapy for LA-HNSCC as well as the ongoing efforts and challenges to determine how to optimally deliver and sequence immunotherapy alongside traditional therapeutics. In both the preclinical and clinical settings, we will discuss the application of immunotherapies to both surgical and radiotherapeutic management of HNSCC