Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed malignancy worldwide, accounting for millions of deaths annually. Despite immune checkpoint inhibitors (ICIs) reported im...

PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: how can they assist drug clinical trials?

Hepatocellular carcinoma (HCC) represents the most commonly diagnosed liver cancer worldwide, and the overall survival of patients with unresectable disease is poor. In the last five years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment scenario of several hematological and solid tumors, and these agents have been actively explored in unresectable HCC. Firstly, promising findings of phase I and II clinical studies reporting durable responses and a tolerable safety profile have led to the assessment of ICIs as single agents in phase III clinical studies; however, the latter have provided controversial results, and the activity of ICI monotherapy seems limited to a small subgroup of patients. Conversely, the IMbrave150 trial recently showed that, among patients with previously untreated unresectable HCC, treatment with atezolizumab plus bevacizumab resulted in significantly longer overall survival and progression-free survival compared to sorafenib monotherapy. In addition, the activity of several other ICIs is under investigation, as combination immunotherapy as well as combinations of immunotherapy with antiangiogenic agents. Nonetheless, there are currently no validated predictive biomarkers able to guide treatment choice in this setting, where the identification of specific predictors of response to ICIs represents a major challenge. In this review, we aim to provide a critical overview of recent evidence on biochemical predictors of response to ICIs in patients with unresectable HCC, especially focusing on PD-L1, TMB, MSI, and other emerging biomarkers.

Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma

ABSTRACT Introduction Hepatocellular carcinoma (HCC) remains a frequently diagnosed malignancy worldwide, still representing an important cause of cancer-related death. Recent years have seen the emergence of novel systemic treatments for HCC patients, including immune checkpoint inhibitors (ICIs). Nonetheless, several questions regarding HCC immunotherapy remain unanswered, especially in terms of biochemical predictors of response. Areas Covered In the current paper, we will discuss available evidence regarding predictive biomarkers of response to HCC immunotherapy. A literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases. Expert Opinion The identification of predictive biomarkers represents an unmet need in HCC patients receiving ICIs. The HCC medical community is called to further efforts aimed to elucidate the effective role of PD-L1 expression, TMB, MSI, gut microbiota, and other emerging biomarkers.

Which role for predictors of response to immune checkpoint inhibitors in hepatocellular carcinoma?

In recent years, with the successful development of proteolysis-targeting chimeric molecules (PROTACs), the potential of heterobifunctional molecules to contribute to reenvisioning drug design, especially small-molecule drugs, has been increasingly recognized. Inspired by PROTACs, diverse heterobifunctional molecules have been reported to simultaneously bind two or more molecules and bring them into proximity to interaction, such as ribonuclease-recruiting, autophagy-recruiting, lysosome-recruiting, kinase-recruiting, phosphatase-recruiting, glycosyltransferase-recruiting, and acetyltransferase-recruiting chimeras. On the basis of the heterobifunctional principle, more opportunities for advancing drug design by linking potential effectors to a protein of interest (POI) have emerged. Herein, we introduce heterobifunctional molecules other than PROTACs, summarize the limitations of existing molecules, list the main challenges, and propose perspectives for future research directions, providing insight into alternative design strategies based on substrate-proximity-based targeting.

Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors.

The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions.

Akt, also known as protein kinase B (PKB), belongs to the AGC family of protein kinases. It acts downstream of the phosphatidylinositol 3-kinase (PI3K) and regulates diverse cellular processes, including cell proliferation, cell survival, metabolism, tumor growth and metastasis. The PI3K/Akt signaling pathway is frequently deregulated in breast cancer and plays an important role in the development and progression of breast cancer. There are three closely related members in the Akt family, namely Akt1(PKBα), Akt2(PKBβ) and Akt3(PKBγ). Although Akt isoforms share similar structures, they exhibit redundant, distinct as well as opposite functions. While the Akt signaling pathway is an important target for cancer therapy, an understanding of the isoform-specific function of Akt is critical to effectively target this pathway. However, our perception regarding how Akt isoforms contribute to the genesis and progression of breast cancer changes as we gain new knowledge. The purpose of this review article is to analyze current literatures on distinct functions of Akt isoforms in breast cancer.

https://www.mdpi.com/2072-6694/13/14/3445/pdf

Akt Isoforms: A Family Affair in Breast Cancer

Higher organisms are all born with general immunity as well as with, increasingly, more specific immune systems. All immune mechanisms function with the intent of aiding the body in defense against infection. Internal and external factors alike have varying effects on the immune system, and the immune response is tailored specifically to each one. Accompanying the components of the human innate and adaptive immune systems are the other intermingling systems of the human body. Increasing understanding of the body's immune interactions with other systems has opened new avenues of study, including that of the microbiome. The microbiome has become a highly active area of research over the last 10 to 20 years since the NIH began funding the Human Microbiome Project (HMP), which was established in 2007. Several publications have focused on the characterization, functions, and complex interplay of the microbiome as it relates to the rest of the body. A dysfunction between the microbiome and the host has been linked to various diseases including cancers, metabolic deficiencies, autoimmune disorders, and infectious diseases. Further understanding of the microbiome and its interaction with the host in relation to diseases is needed in order to understand the implications of microbiome dysfunction and the possible use of microbiota in the prevention of disease. In this review, we have summarized information on the immune system, the microbiome, the microbiome's interplay with other systems, and the association of the immune system and the microbiome in diseases such as diabetes and colorectal cancer.

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Impact of the Microbiome on the Immune System.

Liver cancer is a particularly aggressive group of malignancies with historically low survival rates. Despite advancements in cancer treatments in general in the last few decades, incidence and mortality have not changed. Even though some phase 1 and 2 studies have shown promising results, many medication have failed to reach a sustainable level of efficacy to move into the clinical setting. Immunotherapy drugs have shown impressive results in the treatment of specific immunogenic cancers, prompting the possibility of their use in liver cancers. Immunotherapy medications approved for other cancers have received FDA accelerated approval for treatment of hepatocellular carcinoma. But, these approvals are contingent upon verification and description of clinical benefit in confirmatory trials. With more treatments in development involving cancer vaccines and natural killer cell-mediated therapy, liver cancer treatment is being reinvigorated with a broad array of new treatment angles. In this review article, we discuss these treatments, focusing on mechanism of action and clinical trials. Much needed advancements in treating late- and early-stage liver cancers will require new and innovative immunotherapeutic treatments.

Current Perspectives in Immunotherapy for Liver Cancer.


 Background and Purpose: Copper is a crucial structural component for many significant enzymes, as well as a key catalytic co-factor in redox processes. The flexible Cu(I/II) redox behavior facilitates the formation of copper complexes that are more potent and less toxic. The anticancer activity of several agents can be enhanced by forming copper complexes. The purpose of this study is to evaluate the anti-proliferative effects of two copper (II) complexes, copper-tolfenamic acid (Cu-TA) and copper thiosemicarbazone (Cu-acetylethTSC or CuTSC) against medulloblastoma (MB). MB is a cancer of the cerebellum which is associated with frequent relapse and drug resistance with the current treatments. It necessitates the development of alternative strategies. The anti-cancer activity of Cu-TA was evaluated in laboratory testing in some cancer models, but it has not been studied in MB. CuTSC against colorectal cancer, leukemia and breast cancer has been studied but it has not in MB.
 Methods: TA and TSC were complexed with Cu and Cu-TA and CuTSC complexes were characterized through colorimetric/mass spectrometric analyses. Cancer cells and cardiomyocytes were cultured using standard protocols and cell viability was measured using Cell Titer-Glo kit (Promega). Protein expression was determined by Western blot analysis.
 Experiments/Results: CuTA and CuTSC complexes showed proper characterization and stability during the testing period. Cardiomyocytes (H9C2) and human cancer cell lines representing breast, Ewing sarcoma and MB were screened for anti-proliferative activity of these two Cu complexes. While, cell viability was inhibited in all cancer cell lines, MB cell lines (DAOY and D283) showed higher efficacy while H9C2 cell viability was not affected. To understand the underlying mechanism of action, the effect of Cu-TA was assessed on the expression of c-PARP, Specificity protein 1 (Sp1) and an antiapoptotic protein, survivin. Western blot results revealed a clear decrease in the expression of both Sp1 and survivin and upregulation of c-PARP.
 Discussion/Conclusion: Both Cu-TA and CuTSC treatments result in a dose-time dependent anti-proliferative activity against cancer cells but not affecting non-malignant cardiomyocyte cells. Cu-TA can inhibit Sp1 and survivin and increase PARP cleavage suggesting the effect on Sp1-regulated oncogenes and an induction of apoptotic pathways. The studies to establish crossing of Blood Brain Barrier and further understand the underling mechanisms of these two Cu complexes in single and combination treatment alongside chemotherapeutic agents are currently under investigation.
 Citation Format: Hope Korshie Fiadjoe, Christoffer Lambring, Umesh T. Sankpal, Duaa Alajroush, Alvin A. Holder, Riyaz Basha. Anti-proliferative effect of two copper complexes against medulloblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6255.

Abstract 6255: Anti-proliferative effect of two copper complexes against medulloblastoma cells

Colorectal cancer is the third most prevalent cancer in terms of incidences and cancer-related deaths. Surgery, chemotherapy, and radiation are the standard therapeutic options for several cancers including colorectal cancer. Phytochemicals or derivatives such as taxol and vincristine have shown efficacy and are widely used for the treatment of multiple cancers. Since the toxicity associated with the standard chemotherapeutic agents still is a major concern for treating colorectal cancer, alternative strategies using herbal products are extensively tested. Curcumin (cur) is a product of the plant, Curcuma longa, which exhibits anti-inflammatory, anti-infectious, and anticancer activities. A wide variety of evidences from numerous studies demonstrated that Cur prevents carcinogenesis, modulates signaling, inhibits angiogenesis and other critical aspects linked to cancer cell survival and proliferation, and induces chemopreventive and anticancer activity against colorectal cancer. Cur also showed improved efficacy of chemotherapeutic agents in combination studies. Bioavailability and distribution, and clearance in tissues, pose some limitations for the therapeutic application of this herbal component. To address such limitations, strategies such as combination with other compounds, synthesis of derivatives, and nanoparticles were tested with some success. Overall, Cur could play a vital role in the prevention and therapy of colorectal cancer.

Christoffer Briggs Lambring

Papers

Akt Isoforms: A Family Affair in Breast Cancer

Impact of the Microbiome on the Immune System.

Current Perspectives in Immunotherapy for Liver Cancer.

Abstract 6255: Anti-proliferative effect of two copper complexes against medulloblastoma cells

Therapeutic Effects of Curcumin Against Colorectal Cancer