Classical Chemotherapy Research Articles

Efficacy of IL10/STAT3 directed small molecule immunotherapy in augmenting the potential of rBCG30 vaccine against murine pulmonary tuberculosis

Several recent studies have contributed to our understanding of the need for host directed immunotherapeutic strategies against Mycobacterium tuberculosis ( Mtb ), either concomitantly with classical chemotherapy or also as standalone approach. Nevertheless, most of these studies were focused on enhancing chemotherapeutic potential of standard anti-tuberculosis chemotherapy and only few were aimed towards improving prophylactic immunity offered either by BCG or its potential replacements. In the present study we tried to address the potential gap with the aim to improve anti-TB immunity offered by rBCG30 vaccine. We attempted to bolster rBCG30 invoked anti-TB immunity in mice through modulation of the IL-10/STAT3 interaction mediated anti inflammatory program. An *immunomodulator of IL-10/STAT3 signaling axis was administered in immunized mice to reinforce the anti pathogen capabilities of mononuclear phagocyte system and thereby, to improve T cell mediated secondary immune responses. We envisage that modulation of this crucial praxis may result in reduced expansion of pathogen permissive AAMs/AADCs (Alternatively Activated Monocytes/Macrophages/DCs) and augmented abundance of pro-inflammatory CAMs/CADCs (Classically Activated Monocytes/Macrophages/DCs), the cells that resist establishment of successful Mtb infection. The study was also aimed towards generating optimum activated APCs early either after vaccination or infection, which can process and present mycobacterial antigens more efficiently to T cells.

Is ICI-based therapy better than chemotherapy for metastatic NSCLC patients who develop EGFR-TKI resistance? A real-world investigation

PurposeTo evaluate the outcomes of immune checkpoint inhibitor (ICI)-based treatments versus classical chemotherapy for metastatic non-small cell lung cancer (NSCLC) patients who develop epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance and to explore the population that may benefit from ICI-based therapy.Materials and methodsAll patients who had previously received EGFR-TKI therapy at two cancer centers in China and developed resistance to targeted therapies were included. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of the study cohort.ResultsA total of 132 patients were included. The median follow-up time for this cohort was 21.7 months (IQR, 14.8–28.8 months), calculated from the date of EGFR-TKI resistance. The median PFS and OS were 4.9 months (IQR, 2.8–9.2) and 13.5 months (IQR, 6.6–26.5 months), respectively. Multivariate analysis showed that ICI-based therapy could significantly improve OS when compared to the classic chemotherapy (hazard ratio [HR], 0.55; 95% CI, 0.34–0.88; P = 0.01) after adjusting for variables such as gender, age, mutation status, and brain or liver metastasis status. The combined modality of ICI plus chemotherapy could offer a long-term OS benefit in most subgroups, such as young (<65 years) patients, and those without secondary T790M mutations or absence of liver and brain metastases, and the populations with good Eastern Cooperative Oncology Group (ECOG) scores.ConclusionFor patients presenting with EGFR-TKI resistance, ICI-based therapy could offer a more favorable survival than classical chemotherapy. The combination of ICI with chemotherapy may be the optimal modality for those with good ECOG PS scores.

Nutrition and cancer: modern aspects of a healthy lifestyle (literature review)

Despite significant improvements in screening, diagnosis and targeted therapy, cancer remains the second leading cause of death in the world. It is becoming increasingly clear that diet and lifestyle play a significant role in the development and progression of cancer. Thus, various dietary combinations can be proposed to reduce the risk of cancer and to improve the impact of basic therapy. Nutrition is closely linked to cancer. Food carcinogens, macronutrients, micronutrients such as vitamins A, C and D, dietary fiber, modulation of metabolism by diet, dietary supplements and anticancer agents in food affect the development of cancer. This article discusses research on the relationship between nutrition and cancer, as well as current dietary guidelines for reducing the risk of cancer. The aim of the study is to analyze information from the professional literature on the influence of various nutritional regimes in cancer patients. Conclusions. Proper nutrition can prevent the risk of cancer and improve the impact of treatment on the disease. Ketogenic diet is useful in combination with standard therapy on the basis of its ability to enhance the antitumor effects of classical chemotherapy and radiation therapy, its overall good safety and tolerability, as well as improving the quality of life. Mediterranean diet is a protective factor against cancer, due to the antioxidant and anti-inflammatory properties of the ingredients. Fasting is also a potentially effective strategy for inducing the differential stress resistance of cancer and normal cells as an adjunct to standard treatment. Promising benefits of vitamins in the prevention and treatment of cancer can be achieved through the use of new potent analogues, as well as combinations of vitamins in the early stages of cancer.

Chemotherapy suppresses SHH gene expression via a specific enhancer

Sonic hedgehog (SHH) signaling is a key regulator of embryonic development and tissue homeostasis that is involved in gastrointestinal (GI) cancer progression. Regulation of SHH gene expression is a paradigm of long-range enhancer function. Using the classical chemotherapy drug 5-fluorouracil (5FU) as an example, here we show that SHH gene expression is suppressed by chemotherapy. SHH is downstream of immediate early genes (IEGs), including Early growth response 1 (Egr1). A specific 139 kb upstream enhancer is responsible for its down-regulation. Knocking down EGR1 expression or blocking its binding to this enhancer renders SHH unresponsive to chemotherapy. We further demonstrate that down-regulation of SHH expression does not depend on 5FU's impact on nucleotide metabolism or DNA damage; rather, a sustained oxidative stress response mediates this rapid suppression. This enhancer is present in a wide range of tumors and normal tissues, thus providing a target for cancer chemotherapy and its adverse effects on normal tissues. We propose that SHH is a stress-responsive gene downstream of IEGs, and that traditional chemotherapy targets a specific enhancer to suppress its expression.

Role of Vitamin K in Selected Malignant Neoplasms in Women.

The main function of vitamin K in the human organism is its activity in the blood clotting cascade. Epidemiological studies suggest that reduced intake of vitamin K may contribute to an increased risk of geriatric diseases such as atherosclerosis, dementia, osteoporosis, and osteoarthritis. A growing number of studies also indicate that vitamin K may be involved not only in preventing the development of certain cancers but it may also support classical cancer chemotherapy. This review article summarizes the results of studies on the anticancer effects of vitamin K on selected female malignancies, i.e., breast, cervical, and ovarian cancer, published over the past 20 years. The promising effects of vitamin K on cancer cells observed so far indicate its great potential, but also the need for expansion of our knowledge in this area by conducting extensive research, including clinical trials.

Modern Immunotherapy in the Treatment of Triple-Negative Breast Cancer.

Simple SummaryThis review summarizes reports from the latest clinical trials assessing the safety and clinical effectiveness of new biological drugs stimulating the immune system to fight cancer. The aim of this study is to show the enormous therapeutic potential of monoclonal antibodies in the treatment of cancer, in particular triple negative breast cancer (TNBC). Introduction of these innovative drugs to the standard clinical cancer therapies, including TNBC, allows for an increase in the response rate to the applied treatment, and consequently extending the lives of patients suffering from cancer. We hope to draw attention to the extremely difficult-to-treat TNBC, as well as the importance of the development of clinical trials evaluating drugs modulating the immune system in TNBC therapy.Triple-Negative Breast Cancer is a subtype of breast cancer characterized by the lack of expression of estrogen receptors, progesterone receptors, as well as human epidermal growth factor receptor 2. This cancer accounts for 15–20% of all breast cancers and is especially common in patients under 40 years of age, as well as with the occurring BRCA1 mutation. Its poor prognosis is reflected in the statistical life expectancy of 8–15 months after diagnosis of metastatic TNBC. So far, the lack of targeted therapy has narrowed therapeutic possibilities to classic chemotherapy. The idea behind the use of humanized monoclonal antibodies, as inhibitors of immunosuppressive checkpoints used by the tumor to escape from immune system control, is to reduce immunotolerance and direct an intensified anti-tumor immune response. An abundance of recent studies has provided numerous pieces of evidence about the safety and clinical benefits of immunotherapy using humanized monoclonal antibodies in the fight against many types of cancer, including TNBC. In particular, phase three clinical trials, such as the IMpassion 130, the KEYNOTE-355 and the KEYNOTE-522 resulted in the approval of immunotherapeutic agents, such as atezolizumab and pembrolizumab by the US Food and Drug Administration in TNBC therapy. This review aims to present the huge potential of immunotherapy using monoclonal antibodies directed against immunosuppressive checkpoints—such as atezolizumab, avelumab, durvalumab, pembrolizumab, nivolumab, cemiplimab, tremelimumab, ipilimumab—in the fight against difficult to treat TNBCs as monotherapy as well as in more advanced combination strategies.

Meta of classical chemotherapy compared with high-dose chemotherapy and autologous stem cell rescue in newly diagnosed medulloblastoma after radiotherapy.

Background:High-dose chemotherapy combined with autologous stem cell rescue (HDCT + ASCR) has been used to treat newly diagnosed medulloblastoma, but there was no high-level evidence to support its efficacy.Methods:Databases were retrieved, and patients were divided into 2 groups: group A was radiotherapy combined with HCDT + ASCR, and group B was classical radiotherapy and chemotherapy. The clinical benefit rate, progression-free survival (PFS), overall survival (OS) and toxicities data were extracted.Results:22 clinical trials met the inclusion criteria, 416 in group A and 2331 in group B. There was no difference in CBR between 2 groups (80.0% vs 71.5%, P.262). The 3-year PFS (3-y PFS) of group A was significantly better than group B (79.0% vs 69.5%, P = .004). The analysis found that there was no difference between the 2 groups of the standard risk group or the high-risk group. In the standard risk group, the 5-y PFS of group A was significantly better than group B (83.6% vs75.6%, P = .004). Comparison of 3-y OS and 5-y OS between 2 groups of all MB patients showed no difference (P = .086; P = .507), stratified analysis was the same result. The gastrointestinal toxicity in group A was significantly higher than that in group B (P = .016), and the level 3/4 ototoxicity in high-risk group A was higher than that in group B (P = .001).Conclusions:HDCT + ASCR can prolong 3-year PFS significantly, and prolong 5-y PFS significantly in the standard risk group, but increase gastrointestinal toxicity significantly for newly diagnosed medulloblastoma.

Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress

BackgroundMetabolic adaptations can allow cancer cells to survive DNA-damaging chemotherapy. This unmet clinical challenge is a potential vulnerability of cancer. Accordingly, there is an intense search for mechanisms that modulate cell metabolism during anti-tumor therapy. We set out to define how colorectal cancer CRC cells alter their metabolism upon DNA replication stress and whether this provides opportunities to eliminate such cells more efficiently.MethodsWe incubated p53-positive and p53-negative permanent CRC cells and short-term cultured primary CRC cells with the topoisomerase-1 inhibitor irinotecan and other drugs that cause DNA replication stress and consequently DNA damage. We analyzed pro-apoptotic mitochondrial membrane depolarization and cell death with flow cytometry. We evaluated cellular metabolism with immunoblotting of electron transport chain (ETC) complex subunits, analysis of mitochondrial mRNA expression by qPCR, MTT assay, measurements of oxygen consumption and reactive oxygen species (ROS), and metabolic flux analysis with the Seahorse platform. Global metabolic alterations were assessed using targeted mass spectrometric analysis of extra- and intracellular metabolites.ResultsChemotherapeutics that cause DNA replication stress induce metabolic changes in p53-positive and p53-negative CRC cells. Irinotecan enhances glycolysis, oxygen consumption, mitochondrial ETC activation, and ROS production in CRC cells. This is connected to increased levels of electron transport chain complexes involving mitochondrial translation. Mass spectrometric analysis reveals global metabolic adaptations of CRC cells to irinotecan, including the glycolysis, tricarboxylic acid cycle, and pentose phosphate pathways. P53-proficient CRC cells, however, have a more active metabolism upon DNA replication stress than their p53-deficient counterparts. This metabolic switch is a vulnerability of p53-positive cells to irinotecan-induced apoptosis under glucose-restricted conditions.ConclusionDrugs that cause DNA replication stress increase the metabolism of CRC cells. Glucose restriction might improve the effectiveness of classical chemotherapy against p53-positive CRC cells.Graphical The topoisomerase-1 inhibitor irinotecan and other chemotherapeutics that cause DNA damage induce metabolic adaptations in colorectal cancer (CRC) cells irrespective of their p53 status. Irinotecan enhances the glycolysis and oxygen consumption in CRC cells to deliver energy and biomolecules necessary for DNA repair and their survival. Compared to p53-deficient cells, p53-proficient CRC cells have a more active metabolism and use their intracellular metabolites more extensively. This metabolic switch creates a vulnerability to chemotherapy under glucose-restricted conditions for p53-positive cells.

Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease.

Multiple myeloma (MM) is the most common malignant monoclonal disease of plasma cells. Aside from classical chemotherapy and glucocorticoids, proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are used in the current treatment scheme of MM. The tumor microenvironment (TME) plays a fundamental role in the development and progression of numerous solid and non-solid cancer entities. In MM, the survival and expansion of malignant plasma cell clones heavily depends on various direct and indirect signaling pathways provided by the surrounding bone marrow (BM) niche. In a number of MM patients, single plasma cell clones lose their BM dependency and are capable to engraft at distant body sites or organs. The resulting condition is defined as an extramedullary myeloma (EMM). EMMs are highly aggressive disease stages linked to a dismal prognosis. Emerging literature demonstrates that the dynamic interactions between the TME and malignant plasma cells affect myeloma dissemination. In this review, we aim to summarize how the cellular and non-cellular BM compartments can promote plasma cells to exit their BM niche and metastasize to distant intra-or extramedullary locations. In addition, we list selected therapy concepts that directly target the TME with the potential to prevent myeloma spread.

Abstract 1847: Enhancing the efficacy of conventional chemotherapy with novel targeted small molecules to kill Ewing sarcoma cancer stem-like cells

Abstract Since Ewing sarcoma (ES) is a stem cell-like cancer1, improved outcome for some patients will be realised when treatments to eradicate ES stem-like cells (ES-CSCs) are evaluated in clinical trials. Therefore, we have identified small molecules that kill ES-CSCs, and examined their efficacy alone and in combination with chemotherapy. ES patient-derived cultures and paired ES-CSCs established from treatment-naïve tumors were investigated1. The effect of 1293 small molecules (5µM, 48h) on ES-CSC cell number was examined using high content imaging (Operetta). The effect of the most active small molecules was examined in combination with chemotherapies used to treat ES using high content imaging and CalcuSyn (Biosoft). ES-CSCs were more resistant to chemotherapy than paired patient derived cells (p&amp;lt;0.05)1. In the drug screen, 6% (75/1293) of small molecules were more effective at killing ES-CSCs than doxorubicin. Eight percent (6/75) of the most effective small molecules targeted the Ras/MAPK pathway, including inhibitors of aurora kinases (n=3) and RAS GTPases (n=3). The efficacy of aurora kinase inhibitors, CCT137690 and CD532, was confirmed in 6 ES-CSCs. Patient-derived cells were more sensitive to aurora kinase inhibitors than ES-CSCs (p&amp;lt;0.0001). In combination with chemotherapy, CCT137690 and CD532 synergistically killed patient-derived ES cells (Table 1). We have identified small molecules that kill patient-derived ES-CSCs and confirmed they have synergistic activity with classic chemotherapies, supporting our hypothesis that ES-CSC targeted drugs in combination with existing chemotherapies is a promising therapeutic strategy. 1 Roundhill et al. 2021. Cellular Oncology, 44(5):1065-1085 Table 1. Summary of synergy between the aurora kinase inhibitors and chemotherapeutic agents in 4 patient-derived cell cultures (ES1 - ES4). Patient derived cells were treated with increasing concentrations of chemotherapies and small molecules (0.25x, 0.5x, 2x, 4x the EC50). Concentration range of doxorubicin=0.08-6.7µM, vincristine=0.01-1.5µM, etoposide=0.01-33µM, actinomycin-D=0.02-10µM, carboplatin=8.4-135µM, 4-hyperoxyifosfamide=2.6-152µM, CCT137690=0.07-14µM, CD532=0.05-14µM. Where data is available, concentrations did not exceed the maximum achievable concentration in plasma (Liston and Davis. 2017. Clinical Cancer Research, 15(14):3489-3498). Synergy = combination index &amp;lt;0.9. ES1 ES2 ES3 ES4 CCT137690 (EC50, uM) 3 3.6 0.3 0.4 CD532 (EC50, uM) 1.8 3.5 0.2 1.1 Doxorubicin + CCT137690 Synergy Synergy Synergy Synergy Doxorubicin + CD532 Synergy Synergy Vincristine + CCT137690 Synergy Vincristine + CD532 Synergy Synergy Etoposide + CCT137690 Synergy Synergy Etoposide + CD532 Synergy Synergy Actinomycin-D + CCT137690 Synergy Synergy Actinomycin-D + CD532 Synergy Synergy Synergy Carboplatin + CCT137690 Synergy Synergy Carboplatin + CD532 Synergy Synergy 4-Hyperoxyifosfamide + CCT137690 Synergy Synergy 4-Hyperoxyifosfamide + CD532 Synergy Citation Format: Elizabeth A. Roundhill, Lee Jeys, Michael Parry, Kenneth S. Rankin, Richard Foster, Jacquelyn Bond, Susan Burchill. Enhancing the efficacy of conventional chemotherapy with novel targeted small molecules to kill Ewing sarcoma cancer stem-like cells [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 1847.

The Prevention and Treatment of Nausea and Vomiting During Tumor Therapy.

Nausea and vomiting are common and distressing side effects of tumor therapy. Despite prophylaxis, 40-50% of patients suffer from nausea, and 20-30% from vomiting. Antiemetic prophylaxis and treatment are therefore of great importance for improving patients' quality of life and preventing sequelae such as tumor cachexia. The recommendations presented here are based on international and national guidelines, updated with publications retrieved by a selective search in the PubMed and Cochrane Library databases, with special attention to randomized controlled trials and meta-analyses that have appeared in the past 5 years since the German clinical practice guideline on supportive therapy was published. Risk-adjusted prevention and treatment is based on the identification of treatment-related and patient-specific risk factors, including female sex and younger age. Parenteral tumor therapy is divided into four risk classes (minimal, low, moderate, high), and oral tumor therapy into two (minimal/low, moderate/high). In radiotherapy, the radiation field is of decisive importance. The antiemetic drugs most commonly used are 5-HT3-RA, NK1-RA, and dexamethasone; olanzapine has proven beneficial as an add-on or rescue drug. The use of steroids in patients being treated with drug combinations including checkpoint inhibitors is discussed controversially because of the potentially reduced therapeutic response. Benzodiazepines, dimenhydrinate, and cannabinoids can be used as backup antiemetics. Acupuncture/acupressure, ginger, and progressive muscle relaxation are pos - sible alternative methods. Detailed, effective, risk profile-adapted algorithms for the prevention and treatment of nausea and vomiting are now available for patients undergoing classic chemotherapy regimens or combined radiotherapy and chemotherapy. Optimal symptom control for patients undergoing oral tumor therapy over multiple days in the outpatient setting remains a challenge.

Systematic action-Emergencies in systemic cancer therapy!

HintergrundDie Optionen der medikamentösen Tumortherapie in der Uroonkologie sind in den letzten Jahren sehr vielseitig geworden. Neben klassischer Chemotherapie und Androgendeprivationstherapie werden inzwischen auch Target-Therapie (Tyrosinkinaseinhibitoren), Checkpoint-Inhibitoren und neue Therapieansätze wie die Radioligandentherapie eingesetzt. Egal ob diese Therapien selbst angewendet oder Patienten mitbetreut werden, die Systemtherapie z. B. über die Kollegen andere Fachdisziplinen erhalten, man wird zwangsläufig mit den Komplikationen konfrontiert werden. Dies wird weiter zunehmen, denn stets werden neue Wirkstoffe und teils neue Wirkstoffklassen etabliert. Daher sollte Urolog*innen die Grundzüge der Prophylaxe und Kontrolle der Nebenwirkungen und von Notfallsituationen im Rahmen uroonkologischer Systemtherapie beherrschen.FragestellungWelche uroonkologischen Notfallsituationen sind von Relevanz und was sollte in diesen Situationen unternommen werden.Material und MethodeTypische uroonkologische Notfallsituationen im Rahmen von Systemtherapien werden dargestellt.ErgebnisseUrolog*innen benötigen Expertise im Management von Notfällen während uroonkologischer Systemtherapien wie neutropenem Fieber bei klassischer Chemotherapie, Hand-Fuß-Syndrom unter Tyrosinkinaseinhibitoren, immunvermittelten Nebenwirkungen, aber auch von Nebenwirkungen, die im Rahmen von fachfremder Therapie (wie z. B. der Radioligandentherapie der Nuklearmedizin) auftreten.SchlussfolgerungDies erfordert zumindest grundlegende Kenntnisse der typischen Nebenwirkungen und der sich hieraus ergebenden Notfälle in der uroonkologischen Systemtherapie. Eine regelmäßige Fortbildung zur Beherrschung von neuen Entwicklungen ist in dem sich rapide entwickelnden Feld dringend erforderlich.

Overcoming Resistance to Anti–Nectin-4 Antibody-Drug Conjugate

Antibody-drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4 as a new therapeutic target in breast cancer and produced an efficient EV-like ADC comprising a human anti-nectin-4 mAb conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical breast cancer model in mice, and report a mechanism of resistance to N41mab-vcMMAE after 9-month treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacologic inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. In contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance.

Antibody-Drug Conjugates in Uro-Oncology.

Currently available treatment options for patients with refractory metastatic prostate, bladder, or kidney cancers are limited with the prognosis remaining poor. Advances in the pathobiology of tumors has led to the discovery of cancer antigens that may be used as the target for cancer treatment. Antibody-drug conjugates (ADCs) are a relatively new concept in cancer treatment that broaden therapeutic landscape. ADCs are examples of a 'drug delivery into the tumor' system composed of an antigen-directed antibody linked to a cytotoxic drug that may release cytotoxic components after binding to the antigen located on the surface of tumor cells. The clinical properties of drugs are influenced by every component of ADCs. Regarding uro-oncology, enfortumab vedotin (EV) and sacituzumab govitecan (SG) are currently registered for patients with locally advanced or metastatic urothelial cancer following previous treatment with an immune checkpoint inhibitor (iCPI; programmed death receptor-1 [PD-1] or programmed death-ligand 1 [PD-L1]) inhibitor) and platinum-containing chemotherapy. The EV-301 trial showed that EV significantly prolonged the overall survival compared with classic chemotherapy. The TROPHY-U-01 trial conducted to evaluate SG demonstrated promising results as regards the objective response rate and duration of response. The safety and efficacy of ADCs in monotherapy and polytherapy (mainly with iCPIs) for different cancer stages and tumor types are assessed in numerous ongoing clinical trials. The aim of this review is to present new molecular biomarkers, specific mechanisms of action, and ongoing clinical trials of ADCs in genitourinary cancers. In the expert discussion, we assess the place of ADCs in uro-oncology and discuss their clinical value.

Targeting allosteric regulation of cancer metabolism.

Metabolic reprogramming is observed across all cancer types. Indeed, the success of many classic chemotherapies stems from their targeting of cancer metabolism. Contemporary research in this area has refined our understanding of tumor-specific metabolic mechanisms and has revealed strategies for exploiting these vulnerabilities selectively. Based on this growing understanding, new small-molecule tools and drugs have been developed to study and target tumor metabolism. Here, we highlight allosteric modulation of metabolic enzymes as an attractive mechanism of action for small molecules that target metabolic enzymes. We then discuss the mechanistic insights garnered from their application in cancer studies and highlight the achievements of this approach in targeting cancer metabolism. Finally, we discuss technological advances in drug discovery for allosteric modulators of enzyme activity.

Lucanthone Targets Lysosomes to Perturb Glioma Proliferation, Chemoresistance and Stemness, and Slows Tumor Growth In Vivo.

Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical resection, radiation, temozolomide and tumor-treating fields therapy. After genotoxic stress glioma cells initiate cytoprotective autophagy, which contributes to treatment resistance, limiting the efficacy of these therapies and providing an avenue for glioma recurrence. Antagonism of autophagy steps has recently gained attention as it may enhance the efficacy of classical chemotherapies and newer immune-stimulating therapies. The modulation of autophagy in the clinic is limited by the low potency of common autophagy inhibitors and the inability of newer ones to cross the blood-brain barrier. Herein, we leverage lucanthone, an anti-schistosomal agent which crosses the blood-brain barrier and was recently reported to act as an autophagy inhibitor in breast cancer cells. Our studies show that lucanthone was toxic to glioma cells by inhibiting autophagy. It enhanced anti-glioma temozolomide (TMZ) efficacy at sub-cytotoxic concentrations, and suppressed the growth of stem-like glioma cells and temozolomide-resistant glioma stem cells. In vivo lucanthone slowed tumor growth: reduced numbers of Olig2+ glioma cells, normalized tumor vasculature, and reduced tumor hypoxia. We propose that lucanthone may serve to perturb a mechanism of temozolomide resistance and allow for successful treatment of TMZ-resistant glioblastoma.

Brain metastases from non-small cell lung carcinoma: an overview of classical and novel treatment strategies.

BackgroundThe development of brain metastases is a common problem in patients diagnosed with non-small cell lung carcinoma (NSCLC). Technological advances in surgery and radiotherapy have allowed greater local control. Moreover, the emergence of targeted therapies and immunotherapy with greater activity on the central nervous system than classical chemotherapy have given way to new strategies in the treatment of brain metastases. We review the current role of local treatments, surgery and radiotherapy, and the most effective combination strategies with the new systemic treatments.Relevance for patientsBrain metastases frequently occur during the course of NSCLC. In recent years, a range of treatments have appeared, such as targeted treatments or immunotherapy, with greater activity at the brain level than classical chemotherapy. Radiotherapy treatment is also now much more conformal and ablative doses can be delivered to the volume of the metastatic area, providing greater local control and less neurological toxicity. However, surgery is still required in cases where anatomopathological specimens are needed and when compressive effects appear. An important challenge is how to combine these treatments to achieve the best control and minimise patients’ neurological impairments, especially because of limited experience with the new target drugs, and the unknown toxicity of the different combinations. Future research should therefore focus on these areas in order to establish the best strategies for the treatment of brain metastases from non-small cell lung cancer.Core tipsIn this work, we intend to elucidate the best therapeutic options for patients diagnosed with brain metastases of NSCL, which include: surgery, WBRT, radiosurgery or systemic treatment, and the most effective combinations and timings of them, and the ones with the lowest associated toxicity.

Epigenetic drugs induce the potency of classic chemotherapy, suppress post-treatment re-growth of breast cancer, but preserve the wound healing ability of stem cells

ABSTRACT Epigenetic therapy augments neoadjuvant chemotherapy (NACT) in breast cancer and may aid post-surgical wound healing affected by NACT. Our study investigates: (1) The cytotoxicity of classic paclitaxel chemotherapy on triple negative breast cancer (TNBC) independently and in combination with epigenetic drugs. (2) The sustainable inhibition of breast cancer regrowth following paclitaxel and epigenetic therapies. (3) The effects of paclitaxel with and without epigenetic therapy on the post-treatment viability and wound healing potential of adipose stem cells (ASCs). Cytotoxicity assays were performed on TNBC and ASCs. Cells were treated and recovered in drug-free medium. Cell viability was measured via cell counts and MTT assays. W -ound healing was tested with scratch assays. The combination of epigenetic drugs shows increased toxicity against TNBC cells compared to standard chemotherapy alone. Moreover, the combination of paclitaxel with epigenetic treatments causes cancer toxicity that is sustainable to TNBC cells after the drugs’ removal with minimal effect on ASCs wound healing ability. The use of epigenetic drugs in addition to standard chemotherapy is cytotoxic to TNBC cells and prevents post-treatment recovery of TNBC while maintaining ASC wound healing ability. This strategy may be useful in maximizing post-surgical wound healing following NACT in TNBC.

Molecular Mechanisms of Kaposi Sarcoma Development.

Simple SummaryThere are at least four forms of Kaposi’s sarcoma (KS) with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Kaposi’s sarcoma-associated herpes virus (KSHV) is the underlying cause of this disease. It can infect endothelial and/or mesenchymal cells and establish a latent phase in host cells in which latency proteins and various non-coding RNAs (ncRNAs) play a complex role in proliferation and angiogenesis. It also undergoes periods of sporadic lytic reactivation that are key for KS progression. Complex interactions with the microenvironment with production of inflammatory cytokines and paracrine signaling is a standout feature of KS development and maintenance. KSHV impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines. Treatment options include classical chemotherapy, but other novel therapies are being investigated.Kaposi’s sarcoma (KS) is a heterogeneous angioproliferative tumor that generally arises in the skin. At least four forms of this disease have been described, with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Three quarters of KS cases occur in sub-Saharan Africa (SSA) as geographic variation is explained by the disparate prevalence of KS-associated herpes virus (KSHV), which is the underlying cause of this disease. It can infect endothelial and/or mesenchymal cells that consequently transdifferentiate to an intermediate state. KSHV establishes a latent phase in host cells in which latency proteins and various non-coding RNAs (ncRNAs) play a complex role in proliferation and angiogenesis. It also undergoes periods of sporadic lytic reactivation triggered by various biological signals in which lytic stage proteins modulate host cell signaling pathways and are key in KS progression. Complex interactions with the microenvironment with production of inflammatory cytokines with paracrine signaling is a standout feature of KS development and maintenance. KSHV impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines. Treatment options include classical chemotherapy, but other novel therapies are being investigated.

Collateral responses to classical cytotoxic chemotherapies are heterogeneous and sensitivities are sparse

Chemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity—the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug—has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we evolved over 100 subclones of the Eµ-Myc; p19ARF−/− cell line to be resistant to one of four classical chemotherapy agents: doxorubicin, vincristine, paclitaxel, and cisplatin. We then surveyed collateral responses to acquisition of resistance to these agents. Although numerous collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we observed only one collateral sensitivity: half of cell lines that acquired resistance to paclitaxel also acquired a collateral sensitivity to verapamil. However, we found that the mechanism of this collateral sensitivity was unrelated to the mechanism of paclitaxel resistance. Interestingly, we observed heterogeneity in the phenotypic response to acquisition of resistance to most of the drugs we tested, most notably for paclitaxel, suggesting the existence of multiple different states of resistance. Surprisingly, this phenotypic heterogeneity in paclitaxel resistant cell lines was unrelated to transcriptomic heterogeneity among those cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.