Drug repurposing for cancer therapy, easier said than done.

Drug repurposing for cancer therapy is currently a hot topic of research. Theoretically, in contrast to the known hurdles of developing new molecular entities, the approach of repurposing has several advantages. Mostly, it is said that it is faster, safer, easier, and cheaper. In the real world, however, there are only three repurposed drugs so far, that are listed in widely recognized cancer guidelines, but a large number of them are being studied. Among the many barriers to repurposing cancer drugs, economical-driven are the most important that difficult the clinical development of them. In this review, we provide an overview of the current status of drug repurposing for cancer therapy and the barriers that need to be overcome to realize the benefit of this approach. It means to have repositioned drugs for cancer therapy accepted as standard therapy for cancer indications at low cost.

A Cohort Study of the Prognostic Impact of Exon-16 EZH2 Mutations in a Mexican-Mestizo Population of Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Novel prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) are required in the era of Rituximab. OBJECTIVE: The objective of the study was to study the prognostic impact of exon-16 enhancer-of-zeste homolog-2 (EZH2) mutations in patients with DLBCL. METHODS: In a cohort of patients with DLBCL treated between 2015 and 2017, we analyzed the presence of EZH2 mutations and their association with clinical response (CR), relapse, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 198 patients were included; of them, 30 (15.2%) had mutations at codon 641, in exon 16 of EZH2. Response was achieved in 151 patients (76.3%), and 43 (21.7%) relapsed or progressed during follow-up. EZH2 mutations were associated with relapse/progression (risk ratio [RR] 1.18; 95% confidence interval [CI] 0.98-1.42; p = 0.031), while a trend for not achieving a complete response was observed (RR: 0.876; 95%CI 0.74-1.038; p = 0.071). Of note, Tyr641His and Tyr641Ser EZH2 mutations were associated with shorter PFS (hazard ratio 3.234; 95% CI 1.149-9.1; p = 0.026). CONCLUSION: The presence of EZH2 mutations was negatively associated with relapse/progression and showed a trend for lack of complete response. Further studies are needed to define better the prognostic significance of these mutations in Mexican-Mestizo DLBCL patients.

Late-Onset Hematological Toxicity (LOHT) in Patients with B-Cell Lymphomas: A Survey in 758 Cases.

BACKGROUND: The increasing survival of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term com- plications, including late-onset hematological toxicity (LOHT), transitory cytopenias, or therapy-related myeloid neoplasm (t-MDS/t-AML). OBJECTIVE: The objective of the study was to determine the frequency and clinical evolution of LOHT in patients with lymphoproliferative malignancies. MATERIALS AND METHODS: Two cohorts of patients B-cell lymphomas were reviewed. Patients who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia were included in the study. Clinical and biochemical parameters were compared between patients with and without cytopenias with X2 test. Bi-and multivariate analyses were performed to evaluate factors associated with the development of late-onset cytopenias. RESULTS: Of 758 patients enrolled, 19 developed cytopenias (2.5%). Transitory cytopenia was documented in 6 cases, 3 developed ICUS, 8 t-MDS, and 2 t-AML. In patients with FL, only hemoglobin < 12 g/dL (p = 0.032) and >6 nodal areas (p = 0.037) at diagnosis were factors statistically significant for the development of cytopenia. During cytopenias, 55% of patients died. CONCLUSIONS: LOHT constitutes a cause of morbidity and mortality in 2.5% of lymphoma patients treated with different therapy regimens.

IMMUNOTHERAPY TREATMENT AGAINST CERVICAL CANCER.

Cervical cancer (CC) is one of the most common gynecological tumors and an important health problem, especially in developing countries. The vast majority of patients in early stages are cured of the disease with surgical treatment and with concomitant chemoradiotherapy in locally advanced stages. However, in patients with recurrent, persistent, or metastatic cervical CC, the effectiveness of treatment is limited, except for the combination of chemotherapy based on platinum doublets plus bevacizumab, the treatment that has achieved the best results to date. Programmed cell death-1/PD ligand-1 (PD-1/PD-L1) inhibitors could be a novel and cutting-edge therapeutic option to improve clinical outcomes in this group of patients. Thus far, there are a few Phase I/II clinical trials that have assessed the usefulness of pembrolizumab and nivolumab in this group of patients; these include the KEYNOTE 028, KEYNOTE 158, and CHECKMATE 358 trials, in which clinical benefit has been proven with PD-1/PD-L1 inhibitors in recurrent, persistent, or metastatic CC, as second-line treatment. There are also some ongoing trials that could provide further evidence on the PD-1/PD-L1 pathway as a therapeutic target in CC. In this review, we will focus on the usefulness of these PD-1/PDL1 inhibitors in CC, as well as on trials that are still in the recruitment phase, to confirm their effectiveness in this clinical setting.

Epidemiological Data on the Nutritional Status of Cancer Patients Receiving Treatment with Concomitant Chemoradiotherapy, Radiotherapy or Sequential Chemoradiotherapy to the Abdominopelvic Area.

Cancer patients are particularly susceptible to undernourishment so associated weight loss is frequent. Approximately 15% of patients lose >10% of their usual body weight, 40-80% become undernourished, and about 20% die as a result. Well-nourished patients have a higher survival rate when compared with patients at risk of undernourishment (19.9 vs. 3.7 months); hence, nutritional intervention is pivotal. Undernourishment negatively influences the patient's prognosis, and its prevalence depends on the tumor type and location, disease stage, treatment, and the applied nutritional evaluation tool. During abdominopelvic radiotherapy, up to 90% of patients experience symptoms of varying severity; weight loss during radiotherapy is an early indicator of nutritional deterioration, and he the use of radiation is associated with a higher likelihood of undernourishment. In patients with gynecological malignancies, 12.5-54% are malnourished before receiving oncological treatment, worsening after treatment in 35.8-82% of cases. There is also deterioration of the nutritional status in patients with colorectal cancer once pelvic radiotherapy is initiated, whereby 50% of cases are malnourished at the beginning of treatment, and 66.7% are so when it ends. Although there are notable differences in the impact of radiotherapy on weight according to the radiated region, 88% patients receiving abdominal radiotherapy were found to lose weight compared to 38% of patients whose treatment was limited to the pelvis.

Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIP™) as epigenetic treatment for myelodysplastic syndrome (MDS).

The hypomethylating agents azacytidine and decitabine are unaffordable for many patients with MDS. The combination of the DNA methyltransferase inhibitor hydralazine and the histone deacetylase inhibitor valproate has shown preliminary efficacy in MDS. The aim of this study is to evaluate the clinical efficacy and safety of hydralazine/valproate in a case series of MDS patients treated in a compassionate manner. Hydralazine was dosed according to the acetylation genotype of patients (slow acetylators 83 mg daily; fast acetylators 182 mg daily), and valproate was dosed at 30 mg/kg/day. Both drugs were given daily until disease progression. Response and toxicity were evaluated with the International Working Group criteria and CTCAE, version 4, respectively. Survival parameters were estimated with the Kaplan-Meier method. From 2009 to 2012, 14 patients were treated. The median age ± SD was 55.2 ± 19.52 (range 23-87) years. According to the IPSS, cases were graded as intermediate-1 (n = 8/14; 57.2%) or intermediate-2 (n = 6/14; 42.8%). Responses were as follows: five (35.7%) complete response, one (7.1%) partial response, and two (14.28%) became transfusion independent. The mean duration of response ± SD was 60 ± 35.28 months (range 5-94). Three patients progressed to AML. At a median follow-up of 57 months (range 1-106), the median OS was 27 months. At that point, five patients remained on the treatment, one with partial response and four with complete response. The median OS was not reached in the eight patients who saw a clinical benefit from the treatment, in comparison to an OS of 7 months in the six patients who had no treatment. The combination of hydralazine and valproate is safe and effective in MDS, and its further testing is highly desirable.

Global strategies for the treatment of early-stage and advanced cervical cancer.

PURPOSE OF REVIEW: Recent peer-reviewed publications on the treatment of early, locally advanced and advanced cervical cancer patients are reviewed to gain insight into the main research done in the field. RECENT FINDINGS: In early-stage patients where cure is offered to most patients, research focuses on more conservative or less morbid approaches to increase quality of life and reduce the treatment-related sexual dysfunction. No major advances have occurred for treating locally advanced disease since the introduction of concurrent chemoradiation, but efforts are directed to increase efficacy while reducing toxicity with the use of combination chemoradiation and modern radiation technologies. Molecular-targeted therapy and identification of targetable gene alterations as well as immunotherapy are actively pursued in patients with advanced disease. SUMMARY: Although global statistics indicate a trend for decreased age-standardized incidence rates, social and economical factors impede the uptake of therapeutic advances achieved as many patients have no access even to basic resources for treating cancer. The adherence to quality indicators in delivery of optimized standard concurrent chemoradiation and adherence to guidelines in cervical cancer surgery must not be underestimated. Major efforts are needed in both the scientific and social aspects of cervical cancer treatment to reduce mortality.

N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells.

Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC50 (µM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.

G80A Single Nucleotide Polymorphism in Reduced Folate Carrier-1 Gene in a Mexican Population and its Impact on Survival in Patients with Acute Lymphoblastic Leukemia.

BACKGROUND: Hyper-CVAD is the treatment for patients with acute lymphoblastic leukemia in our institution. OBJECTIVE: To evaluate the impact of single nucleotide polymorphisms at genes associated with methotrexate metabolism on survival. METHODS: The presence of the single nucleotide polymorphisms G80A at reduced folate carrier-1 gene and C677T in the methylenetetrahydrofolate reductase gene was determined by denaturing high performance liquid chromatography and validated by sequencing. Both single nucleotide polymorphisms were evaluated in 71 healthy donors and in an exploratory pilot trial with acute lymphoblastic leukemia patients to determine the influence of these single nucleotide polymorphisms on clinical outcome. Clinical characteristics, response, and outcome were registered. A Cox regression analysis was done to evaluate factors influencing response and overall survival. RESULTS: There were no differences in the frequency of single nucleotide polymorphisms between volunteers and acute lymphoblastic leukemia patients according to the Hardy-Weinberg test. Sensitivity and specificity were 72 and 91% for the G80A, and 64 and 75% for the C677T, respectively. The multivariate analysis showed that the T-immunophenotype and the presence of single nucleotide polymorphism G80A reduced folate carrier-1 were associated with a shorter relapse-free survival and overall survival. CONCLUSIONS: The presence of G80A single nucleotide polymorphism at reduced folate carrier-1 gene in acute lymphoblastic leukemia patients was associated with a poorer prognosis.

Emerging drugs for the treatment of cervical cancer.

INTRODUCTION: Worldwide, most cervical cancer (CC) patients require the use of drug therapy either adjuvant, concurrent with radiation or palliative. AREAS COVERED: This review briefly discusses the current achievements in treating CC with an emphasis in emerging agents. EXPERT OPINION: Concurrent cisplatin with radiation and lately, gemcitabine-cisplatin chemoradiation has resulted in small but significant improvements in the treatment of locally advanced and high-risk early-stage patients. So far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and encouraging results in a Phase II study. In advanced disease, cisplatin doublets yield median survival rates not exceeding 14 months. The first Phase III study of bevacizumab, added to standard chemotherapy cisplatin- or non-cisplatin-containing doublet, has shown significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. The characterization of the mutational landscape of CC and developments of novel targeted therapies may result in more effective and individualized treatments for CC. The potential efficacy of knocking down the key alterations in CC, E6 and E7 human papilloma virus oncoproteins must not be overlooked.

Planning cancer control in Latin America and the Caribbean.

Non-communicable diseases, including cancer, are overtaking infectious disease as the leading health-care threat in middle-income and low-income countries. Latin American and Caribbean countries are struggling to respond to increasing morbidity and death from advanced disease. Health ministries and health-care systems in these countries face many challenges caring for patients with advanced cancer: inadequate funding; inequitable distribution of resources and services; inadequate numbers, training, and distribution of health-care personnel and equipment; lack of adequate care for many populations based on socioeconomic, geographic, ethnic, and other factors; and current systems geared toward the needs of wealthy, urban minorities at a cost to the entire population. This burgeoning cancer problem threatens to cause widespread suffering and economic peril to the countries of Latin America. Prompt and deliberate actions must be taken to avoid this scenario. Increasing efforts towards prevention of cancer and avoidance of advanced, stage IV disease will reduce suffering and mortality and will make overall cancer care more affordable. We hope the findings of our Commission and our recommendations will inspire Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies.

Selection of clinically relevant drug concentrations for in vitro studies of candidates drugs for cancer repurposing: a proposal.

Drug repurposing of widely prescribed patent-off and cheap drugs may provide affordable drugs for cancer treatment. Nevertheless, many preclinical studies of cancer drug repurposing candidates use in vitro drug concentrations too high to have clinical relevance. Hence, preclinical studies must use clinically achievable drug concentrations. In this work, several FDA-approved cancer drugs are analyzed regarding the correlation between the drug inhibitory concentrations 50% (IC50) tested in cancer cell lines and their corresponding peak serum concentration (Cmax) and area under the curve (AUC) reported in clinical studies of these drugs. We found that for most targeted cancer drugs, the AUC and not the Cmax is closest to the IC50; therefore, we suggest that the initial testing of candidate drugs for repurposing could select the AUC pharmacokinetic parameter and not the Cmax as the translated drug concentration for in vitro testing. Nevertheless, this is a suggestion only as experimental evidence does not exist to prove this concept. Studies on this issue are required to advance in cancer drug repurposing.

MULTITARGETED POLYPHARMACOTHERAPY for CANCER TREATMENT. THEORETICAL CONCEPTS and PROPOSALS.

INTRODUCTION: . The pharmacological treatment of cancer has evolved from cytotoxic to molecular targeted therapy. The median survival gains of 124 drugs approved by the FDA from 2003 to 2021 is 2.8 months. Targeted therapy is based on the somatic mutation theory, which has some paradoxes and limitations. While efforts of targeted therapy must continue, we must study newer approaches that could advance therapy and affordability for patients. AREAS COVERED: This work briefly overviews how cancer therapy has evolved from cytotoxic chemotherapy to current molecular-targeted therapy. The limitations of the one-target, one-drug approach considering cancer as a robust system and the basis for multitargeting approach with polypharmacotherapy using repurposing drugs. EXPERT OPINION: Multitargeted polypharmacotherapy for cancer with repurposed drugs should be systematically investigated in preclinical and clinical studies. Remarkably, most of these proposed drugs already have a long history in the clinical setting, and their safety is known. In principle, the risk of their simultaneous administration should not be greater than that of a first-in-human phase I study as long as the protocol is developed with strict vigilance to detect early possible side effects from their potential interactions. Research on cancer therapy should go beyond the prevailing paradigm targeted therapy.

A randomized comparison of cisplatin and oral vinorelbine as radiosensitizers in aged or comorbid locally advanced cervical cancer patients.

OBJECTIVE: Chemoradiation with cisplatin is considered the standard of care for patients with locally advanced cervical cancer; however, cisplatin could be difficult to use in aged patients or patients with comorbidities such as diabetes mellitus and blood hypertension; hence, it is important to investigate nonplatinum drugs for radiosensitization. In addition, oral cytotoxics may overcome the drawbacks of intravenous infusions and could be of easier administration. METHODS: In this small randomized trial, we tested cisplatin against oral vinorelbine as radiosensitizers in these patients. A total of 39 patients 65 years or older or diabetic and hypertensive patients of any age were randomized to cisplatin or oral vinorelbine at 40 mg/m² or 60 mg/m², respectively. Both drugs were administered weekly for 6 courses during pelvic external-beam radiotherapy and brachytherapy radiation. Efficacy and safety were assessed. RESULTS: Nineteen patients received oral vinorelbine, and 20 patients received cisplatin. The median cumulative dose to point A was 80.8 Gy for both groups, and the overall treatment time was 48 (42-54) and 50 (43-55) days for vinorelbine and cisplatin groups, respectively. Patients in both arms received a median of 5 applications of chemotherapy. Treatment was well tolerated in both arms. The most frequent toxicity in both arms was lymphopenia grades 2 and 3. At a median follow-up time of 16 months (4-19), there were no differences in either progression-free survival or overall survival between groups. CONCLUSIONS: Our results suggest that these patient populations can safely be treated with either cisplatin or navelbine as radiosensitizers; however, a larger randomized study is needed to demonstrate the noninferiority of oral vinorelbine as an easier and practical alternative for radiosensitization in cervical cancer.

Combinational therapies for the treatment of advanced cervical cancer.

INTRODUCTION: From a therapeutic standpoint, invasive cervical cancer can be designated as early, locally advanced, and advanced stages. Systemic treatment remains the primary therapeutical modality for advanced cervical cancer patients who are not candidates for local curative treatments (surgery and radiation). AREAS COVERED: In this review, the author discusses recent clinical studies published in PubMed on the treatment of advanced cervical carcinoma. The author also provides his expert perspectives on the current state of play. EXPERT OPINION: Survival outcomes for advanced cervical cancer patients have been steadily improving since 1981, when single-agent cisplatin was adopted as the standard of care. In 2014, bevacizumab increased median overall survival (MOS) to 17 months when combined with standard chemotherapy (platinum-paclitaxel). In 2021, the checkpoint inhibitor (CPI) pembrolizumab, when used in the first line added to platinum-paclitaxel-bevacizumab, increased mOS to 24 months. Two other CPIs are in phase III trials as first-line treatments. As for second-line therapy, cemiplimab has shown increased survival compared to single-agent chemotherapy, and a phase III trial with tisotumab vedotin is currently ongoing. Nevertheless, there is still an unmet need for new more effective treatments and significant efforts are needed in the discovery of drugs for advanced cervical cancer beyond the current 'me-too' drugs.

Does Therapeutic Repurposing in Cancer Meet the Expectations of Having Drugs at a Lower Price?

Therapeutic repurposing emerged as an alternative to the traditional drug discovery and development model (DDD) of new molecular entities (NMEs). It was anticipated that by being faster, safer, and cheaper, the development would result in lower-cost drugs. As defined in this work, a repurposed cancer drug is one approved by a health regulatory authority against a non-cancer indication that then gains new approval for cancer. With this definition, only three drugs are repurposed for cancer: Bacillus Calmette-Guerin (BCG) vaccine (superficial bladder cancer, thalidomide [multiple myeloma], and propranolol [infantile hemangioma]). Each of these has a different history regarding price and affordability, and it is not yet possible to generalize the impact of drug repurposing on the final price to the patient. However, the development, including the price, does not differ significantly from an NME. For the end consumer, the product's price is unrelated to whether it followed the classical development or repurposing. Economic constraints for clinical development, and drug prescription biases for repurposing drugs, are barriers yet to be overcome. The affordability of cancer drugs is a complex issue that varies from country to country. Many alternatives for having affordable drugs have been put forward, however these measures have thus far failed and are, at best, palliative. There are no immediate solutions to the problem of access to cancer drugs. It is necessary to critically analyze the impact of the current drug development model and be creative in implementing new models that genuinely benefit society.

PaSTe. Blockade of the Lipid Phenotype of Prostate Cancer as Metabolic Therapy: A Theoretical Proposal.

BACKGROUND: Prostate cancer is the most frequently diagnosed malignancy in 112 countries and is the leading cause of death in eighteen. In addition to continuing research on prevention and early diagnosis, improving treatments and making them more affordable is imperative. In this sense, the therapeutic repurposing of low-cost and widely available drugs could reduce global mortality from this disease. The malignant metabolic phenotype is becoming increasingly important due to its therapeutic implications. Cancer generally is characterized by hyperactivation of glycolysis, glutaminolysis, and fatty acid synthesis. However, prostate cancer is particularly lipidic; it exhibits increased activity in the pathways for synthesizing fatty acids, cholesterol, and fatty acid oxidation (FAO). OBJECTIVE: Based on a literature review, we propose the PaSTe regimen (Pantoprazole, Simvastatin, Trimetazidine) as a metabolic therapy for prostate cancer. Pantoprazole and simvastatin inhibit the enzymes fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), therefore, blocking the synthesis of fatty acids and cholesterol, respectively. In contrast, trimetazidine inhibits the enzyme 3-b-Ketoacyl-CoA thiolase (3-KAT), an enzyme that catalyzes the oxidation of fatty acids (FAO). It is known that the pharmacological or genetic depletion of any of these enzymes has antitumor effects in prostatic cancer. RESULTS: Based on this information, we hypothesize that the PaSTe regimen will have increased antitumor effects and may impede the metabolic reprogramming shift. Existing knowledge shows that enzyme inhibition occurs at molar concentrations achieved in plasma at standard doses of these drugs. CONCLUSION: We conclude that this regimen deserves to be preclinically evaluated because of its clinical potential for the treatment of prostate cancer.

Emerging drugs for cervical cancer.

INTRODUCTION: There is a shortage of therapeutical agents for invasive cervical cancer in late stages of development; however, a number of promising molecules are currently in early phases of development. AREAS COVERED: This review briefly discusses the current achievements in treating cervical cancer with an emphasis in emerging agents based on a literature search on pubmed and related sites for cervical cancer information. This is not a systematic review. EXPERT OPINION: In advanced disease, modest survival gains have been achieved with cisplatin doublets. Contrariwise, chemoradiation has increased survival rates in locally advanced disease, but there is still room for improvement. Anti-vascular endothelial growth factor and anti-epidermal growth factor receptor monoclonal antibodies are promising molecules that are at present in late-phase development, but a high number of miscellaneous agents are in early development. Strong experimental bases support that the 'Achilles' heel' of cervical cancer are the HPV-E6/E7 oncogenes. Unfortunately, agents aimed at targeting these cervical cancer-driven players are found in very early development; hence, major research efforts must be focused on developing technological strategies for their effective targeting using nucleic acid-based vehicles for safe and effective delivery to cancer cells as well as accelerating the search for small-molecule inhibitors of E6/E7 themselves or their interacting cellular proteins.

Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications.

BACKGROUND: Worldwide, gastric cancer is ranked the fifth malignancy in incidence and the third malignancy in mortality. Gastric cancer causes an altered metabolism that can be therapeutically exploited. OBJECTIVE: The objective of this study is to provide an overview of the significant metabolic alterations caused by gastric cancer and propose a blockade. METHODS: A comprehensive and up-to-date review of descriptive and experimental publications on the metabolic alterations caused by gastric cancer and their blockade. This is not a systematic review. RESULTS: Gastric cancer causes high rates of glycolysis and glutaminolysis. There are increased rates of de novo fatty acid synthesis and cholesterol synthesis. Moreover, gastric cancer causes high rates of lipid turnover via fatty acid ß-oxidation. Preclinical data indicate that the individual blockade of these pathways via enzyme targeting leads to antitumor effects in vitro and in vivo. Nevertheless, there is no data on the simultaneous blockade of these five pathways, which is critical as tumors show metabolic flexibility in response to the availability of nutrients. This means tumors may activate alternate routes when one or more are inhibited. We hypothesize there is a need to simultaneously block them to avoid or decrease the metabolic flexibility that may lead to treatment resistance. CONCLUSION: There is a need to explore the preclinical efficacy and feasibility of combined metabolic therapy targeting the pathways of glucose, glutamine, fatty acid synthesis, cholesterol synthesis, and fatty acid oxidation. This may have therapeutical implications because we have clinically available drugs that target these pathways in gastric cancer.

The health system and access to treatment in patients with cervical cancer in Mexico.

Cervical cancer (CC) is tightly related to a low Human Development Index. Mexico is an upper-middle-income country with 126 million inhabitants, and its public health system aims to provide universal health coverage. Currently, employment-based social insurance covers approximately 60% of the population, and the scope of the remaining 40% is on course via the "IMSS-Bienestar" Institute. However, the annual government spending on health remains at 3% of the Gross Domestic Product, which is well below the 6% recommended by the Organization for Economic Cooperation and Development. CC is the second in incidence and mortality among women. Regarding primary prevention with the Human Papilloma Virus-vaccine, the current coverage for girls aged 9 to 14 years is only around 7%. Among secondary prevention with screening, the program is yet to cover the total number of women at risk; nevertheless, the age-standardized CC mortality rate has decreased from 12 per 100,000 women in 1979 to 5.7 per 100,000 women in 2020 due in part to increased screening coverage. Still, around two-thirds of patients present with locally advanced disease at diagnosis. Data from our country demonstrate that even socially disadvantaged CC patients achieve "standard" survival outcomes if treatment is granted. Nevertheless, there is a shortage in almost every aspect regarding CC treatment, including oncologists, chemotherapy units, medical physicists, radiation technicians, and both teletherapy and brachytherapy facilities. In conclusion, advances in the public health system in Mexico are urgently required to achieve CC control and reduce the mortality from this neoplasia that mainly targets socially disadvantaged women.