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Absence of Biomarker-Driven Treatment Options in Small Cell Lung Cancer, and Selected Preclinical Candidates for Next Generation Combination Therapies.

Lung cancer is the second most common cancer in the United States, and small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. In SCLC, more than other malignancies, the standard of care is based on clinical demonstration of efficacy, and less on a mechanistic understanding of why certain treatments work better than others. This is in large part due to the virulence of the disease, and lack of clinically or biologically relevant biomarkers beyond routine histopathology. While first line therapies work in the majority of patients with extensive stage disease, development of re

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… Q., Qi Y., Koczywas M., Argiris A., Johnson E. A., Millward M. J., et al. (2011). A Phase II Study of AT-101 (Gossypol) in Chemotherapy-Sensitive Recurrent Extensive-Stage Small Cell Lung Cancer. J. Thorac. Oncol. 6 (10), 1757–1760. 10.1097/JTO.0b013e31822e2941 Belani C. P., Dahlberg S. …

Recent Progress of Exosomes in Multiple Myeloma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological malignancy that is still incurable. The bone marrow microenvironment (BMM), with cellular and non-cellular components, can create a favorable environment for the survival, proliferation and migration of MM cells, which is the main reason for the failure of MM therapies. Many studies have demonstrated that exosomes play an important role in the tumor-supportive BMM. Exosomes are nanoscale vesicles that can be released by various cells. Some exosomes contribute to the pathogenesis and progression of MM. MM-derived exosomes act on different cells in the BM

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… Lu Z., Zuo B., Jing R., Gao X., Rao Q., Liu Z., Qi H., Guo H., Yin H. Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models. J. Hepatol. 2017;67:739–748. doi: 10.1016/j.jhep.2017.05.019. 88. …

The Role of Monoclonal Antibodies in the Era of Bi-Specifics Antibodies and CAR T Cell Therapy in Multiple Myeloma.

Multiple myeloma (MM) remains largely incurable despite enormous improvement in the outcome of patients. Over the past decade, we have witnessed the "era of monoclonal antibody (moAb)", setting new benchmarks in clinical outcomes for relapsed and newly diagnosed MM. Due to their excellent efficacy and relative safe toxicity profile, moAbs in combination with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have become the new backbone of upfront anti-MM therapy. Yet, most patients will eventually relapse and patients who become refractory to IMiDs, PIs and moAbs have a dismal out

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… Qi K. Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study Br. J. Haematol. 2019 185 492 502 10.1111/bjh.15806 30828799 PMC6593455 27. O’Dwyer M. Henderson R. Naicker S.D. Cahill M.R. Murphy P. Mykytiv V. Quinn J. McEllistrim C. …

Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

β-glucans represent a heterogeneous group of naturally occurring and biologically active polysaccharides found in many kinds of edible mushrooms, baker's yeast, cereals and seaweeds, whose health-promoting effects have been known since ancient times. These compounds can be taken orally as food supplements or as part of daily diets, and are safe to use, nonimmunogenic and well tolerated. A main feature of β-glucans is their capacity to function as biological response modifiers, exerting regulatory effects on inflammation and shaping the effector functions of different innate and adaptive immuni

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… Qi C. beta-Glucan enhances cytotoxic T lymphocyte responses by activation of human monocyte-derived dendritic cells via the PI3K/AKT pathway Hum. Immunol. 2015 76 146 154 10.1016/j.humimm.2015.01.009 25636576 54. Cardone M. Dzutsev A.K. Li H. Riteau N. Gerosa F. Shenderov K. Winkler-Pickett R. …

Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis.

Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a

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… Concha N.O., Smallwood A., Bonnette W., Totoritis R., Zhang G., Federowicz K., Yang J., Qi H., Chen S., Campobasso N., et al. Long-Range Inhibitor-Induced Conformational Regulation of Human IRE1α Endoribonuclease Activity. Mol. Pharmacol. 2015;88:1011–1023. doi: 10.1124/mol.115.100917. 33. …

Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia.

Epigenetic alteration has been proposed to give rise to numerous classic hallmarks of cancer. Impaired DNA methylation plays a central role in the onset and progression of several types of malignancies, and DNA methylation is mediated by DNA methyltransferases (DNMTs) consisting of DNMT1, DNMT3A, and DNMT3B. DNMTs are frequently implicated in the pathogenesis and aggressiveness of acute myeloid leukaemia (AML) patients. In this review, we describe and discuss the oncogenic roles of DNMT1, DNMT3A, and DNMT3B in AML. The clinical response predictive roles of DNMTs in clinical trials utilising hy

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… Shu Y, Zhou X, Qi X, et al. β-Arrestin1 promotes the self-renewal of the leukemia-initiating cell-enriched subpopulation in B-lineage acute lymphoblastic leukemia related to DNMT1 activity. Cancer Lett. 2015;357:170–178. 44. Wang J, Hua L, Guo M, et al. …

Killing me softly--future challenges in apoptosis research.

The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting areas currently investigated and that will need to be better understood in order to enhance the efficacy of therapeutic measures. First, we discuss which target to select for cancer therapy and argue that not the cancer cell as such, but its interaction with the microenvironment is a more promising and genetically stable site of attack. Second, the

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… Kiziltepe T., Ashley J.D., Stefanick J.F., Qi Y.M., Alves N.J., Handlogten M.W., Suckow M.A., Navari R.M., Bilgicer B. Rationally engineered nanoparticles target multiple myeloma cells overcome cell-adhesion-mediated drug resistance and show enhanced efficacy in vivo. …

Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles.

Cytokines are essential components of the tumor microenvironment (TME) and play crucial roles in tumor initiation and progression. As key mediators of interactions between immune cells and tumor cells within the TME, many cytokines exhibit both protumor and antitumor properties. This complex duality, reminiscent of the balance philosophy pursued by "Onmyoji" in traditional Eastern philosophy, which involves observing and regulating opposing forces to achieve harmony, poses marked challenges in translating cytokine therapies from animal studies to clinical applications. More than 20 key cytokin

A Holistic Review of Oncological Drug Targets and Trajectories of Resistance in Cancer Therapy.

The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy. Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies. Human epidermal growth factor receptor, hormone receptors, and angiogenesis factors are among the established therapies in tumor reduction and managing side effects. Novel targeted therapies like KRAS G12C, Claudin-18 isoform 2 (CLDN18.2), Trophoblast cell-surface antigen 2 (TROP2), and epigenetic r

Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.

Post-translational modifications (PTMs) play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality. PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short-chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation

Artificial Intelligence for Risk Stratification in Diffuse Large B-Cell Lymphoma: A Systematic Review of Classification Models and Predictive Performances.

Background: Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous malignancy, with various outcomes despite significant advances in therapeutic options. Current conventional prognostic tools, e.g., the International Prognostic Index (IPI), lack sufficient precision at an individual patient level. However, artificial intelligence (AI), including machine learning (ML) and deep learning (DL), can enable specialists to navigate complex datasets, with the final aim of improving prognostic models for DLBCL. Objectives: This scoping review aims to systematically map the current litera

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… FL classification | Accuracy = 100% (EBPSO); signature = 5 genes; runtime = 684 s (vs. 1447 s for BPSO); smaller gene sets | 10 repeated runs; compared EBPSO and BPSO on same system; evaluated stability, parsimony, and reproducibility Qi (2022) [ 62 ] | Gene expression (microarray) | Training: 432 samples …

Metabolic reprogramming in cancer and senescence.

The rising trend in global cancer incidence has caused widespread concern, one of the main reasons being the aging of the global population. Statistical data show that cancer incidence and mortality rates show a clear upward trend with age. Although there is a commonality between dysregulated nutrient sensing, which is one of the main features of aging, and metabolic reprogramming of tumor cells, the specific regulatory relationship is not clear. This manuscript intends to comprehensively analyze the relationship between senescence and tumor metabolic reprogramming; as well as reveal the impac

The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs.

Over the past decade, chronic lymphocytic leukaemia (CLL) treatment has shifted from chemoimmunotherapy to targeted oral agents, predominantly Bruton's tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax. These therapies have significantly improved outcomes and are now established as first-line treatment options. However, CLL remains incurable, and resistance or intolerance to both drug classes (double-refractory disease) is an emerging challenge. This has driven the development of novel therapeutic strategies, including non-covalent BTKis such as pirtobrutinib and nemtabruti

One step further in targeting acute leukemia by combining antibody-based immunotherapies and small molecule inhibitors.

BackgroundAcute leukemia is a bone marrow-related disease characterized by fast progression and the production of immature blood cells rather than normal ones that are classified as either acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Chemotherapy as a conventional treatment has many side effects, thus new medications that target intracellular molecules and cell surface markers on leukemic cells have been developed in the last decades.Main bodyThis review focuses on antibody-based targeted treatments, which so far, have been shown to improve the treatment outcomes, includ

Unveiling the role of histone deacetylases in neurological diseases: focus on epilepsy.

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators re

Infusion and delivery strategies to maximize the efficacy of CAR-T cell immunotherapy for cancers.

Chimeric antigen receptor (CAR) T-cell therapy has achieved substantial clinical outcomes for tumors, especially for hematological malignancies. However, extending the duration of remission, reduction of relapse for hematological malignancies and improvement of the anti-tumor efficacy for solid tumors are challenges for CAR-T cells immunotherapy. Besides the endeavors to enhance the functionality of CAR-T cell per se, optimization of the infusion and delivery strategies facilitates the breakthrough of the hurdles that limited the efficacy of this cancer immunotherapy. Here, we summarized the i

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… Qi C Gong J Li J Liu D Qin Y Ge S Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results Nat Med 2022 28 6 1189 98 10.1038/s41591-022-01800-8 35534566 PMC9205778 Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, et al. …

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Unders

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… Qi M., Philip M.C., Yang N., Sweedler J.V. Single Cell Neurometabolomics. ACS Chem. Neurosci. 2018;9:40–50. doi: 10.1021/acschemneuro.7b00304. 11. Lombard-Banek C., Li J., Portero E.P., Onjiko R.M., Singer C.D., Plotnick D.O., Al Shabeeb R.Q., Nemes P. …

Using ncRNAs as Tools in Cancer Diagnosis and Treatment-The Way towards Personalized Medicine to Improve Patients' Health.

Although the first discovery of a non-coding RNA (ncRNA) dates back to 1958, only in recent years has the complexity of the transcriptome started to be elucidated. However, its components are still under investigation and their identification is one of the challenges that scientists are presently facing. In addition, their function is still far from being fully understood. The non-coding portion of the genome is indeed the largest, both quantitatively and qualitatively. A large fraction of these ncRNAs have a regulatory role either in coding mRNAs or in other ncRNAs, creating an intracellular

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… Qi C. Ge J. MicroRNAs in Alzheimer’s disease: Potential diagnostic markers and therapeutic targets Biomed. Pharmacother. 2022 148 12681 10.1016/j.biopha.2022.112681 35177290 36. Ala U. …

Statins: a repurposed drug to fight cancer.

As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subt

Immunotherapy in Multiple Myeloma.

Multiple myeloma is a complex disease and immune dysfunction has been known to play an important role in the disease pathogenesis, progression, and drug resistance. Recent efforts in drug development have been focused on immunotherapies to modify the MM disease process. Here, we summarize the emerging immunotherapies in the MM treatment landscape.