Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Exploiting synergy: immune-based combinations in the treatment of prostate cancer.

ABSTRACT: Cancer treatment is being revolutionized by the emergence of immunotherapies such as immune checkpoint inhibitors and therapeutic cancer vaccines. Prostate cancer is amenable to such therapeutic approaches. The improved understanding of the relationship between the immune system and tumors has allowed therapeutic targeting of immune checkpoints and tumor associated antigens to be developed. Furthermore, interventions used in prostate cancer are capable of impacting the immune system. As demonstrated by preclinical data and emerging clinical data, radiation therapy, anti-androgen therapy, and chemotherapy can be used with immunotherapies to obtain synergistic results. Current and future clinical trials will further investigate these principles as immunotherapeutics are combined with each other and standard therapies for optimal clinical utility.

SUBMITTER: Burotto M

PROVIDER: S-EPMC4264488 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Exploiting synergy: immune-based combinations in the treatment of prostate cancer.

Burotto Mauricio M Singh Nishith N Heery Christopher R CR Gulley James L JL Madan Ravi A RA

Frontiers in oncology 20141212

Cancer treatment is being revolutionized by the emergence of immunotherapies such as immune checkpoint inhibitors and therapeutic cancer vaccines. Prostate cancer is amenable to such therapeutic approaches. The improved understanding of the relationship between the immune system and tumors has allowed therapeutic targeting of immune checkpoints and tumor associated antigens to be developed. Furthermore, interventions used in prostate cancer are capable of impacting the immune system. As demonstr ...[more]

PMID: 25566495

Similar Datasets

Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment.

Project description:The PI3K/AKT/mTOR signaling is important for cell proliferation, survival, and metabolism. Hyperactivation of this pathway is one of the most common signaling abnormalities observed in cancer and a substantial effort has recently been made to develop molecules targeting this signaling cascade. However, it is becoming evident that PI3K inhibitors used as single agents do not elicit dramatic or durable responses. Given the numerous mechanisms mediating intrinsic and acquired resistance to these agents, hypothesis-based combinatorial strategies are probably needed to fully exploit their antitumor activity. In the first part of this review, we briefly dissect the PI3K/AKT/mTOR axis and list the most advanced compounds targeting different nodes of this cascade. The second part focuses on what we believe to be the most promising rationale-based therapeutic combinations with PI3K/AKT/mTOR inhibitors in solid tumors, with special emphasis on breast cancer.

| S-EPMC4904898 | biostudies-other

Exploiting Epigenetic Alterations in Prostate Cancer.

Project description:Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

| S-EPMC5454930 | biostudies-literature

Treatment Combinations with DNA Vaccines for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC).

Project description:Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease to treat, with poor outcomes for patients. One antitumor vaccine, sipuleucel-T, has been approved as a treatment for mCRPC. DNA vaccines are another form of immunotherapy under investigation. DNA immunizations elicit antigen-specific T cells that cause tumor cell lysis, which should translate to meaningful clinical responses. They are easily amenable to design alterations, scalable for large-scale manufacturing, and thermo-stable for easy transport and distribution. Hence, they offer advantages over other vaccine formulations. However, clinical trials with DNA vaccines as a monotherapy have shown only modest clinical effects against tumors. Standard therapies for CRPC including androgen-targeted therapies, radiation therapy and chemotherapy all have immunomodulatory effects, which combined with immunotherapies such as DNA vaccines, could potentially improve treatment. In addition, many investigational drugs are being developed which can augment antitumor immunity, and together with DNA vaccines can further enhance antitumor responses in preclinical models. We reviewed the literature available prior to July 2020 exploring the use of DNA vaccines in the treatment of prostate cancer. We also examined various approved and experimental therapies that could be combined with DNA vaccines to potentially improve their antitumor efficacy as treatments for mCRPC.

| S-EPMC7601088 | biostudies-literature

PARP inhibitor combinations in prostate cancer.

Project description:Polyadenosine-diphosphate-ribose polymerase (PARP) inhibitors cause deoxyribonucleic acid (DNA) damage that can be lethal to cells with deficient repair mechanisms. A number of PARP inhibitors are being tested as treatments for men with prostate cancer, both as monotherapies and in combinations that are based on purported synergies in treatment effect. While the initial single-agent development focused on men with identified deficiencies in DNA-repair pathways, broader patient populations are being considered for combination approaches. This review summarizes the current clinical development of PARP inhibitors and explores the rationale for novel combination strategies.

| S-EPMC7081465 | biostudies-literature

Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.

Project description:Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.

| S-EPMC3882219 | biostudies-literature

Quantifying subpopulation synergy for antibiotic combinations via mechanism-based modeling and a sequential dosing design.

Project description:Quantitative modeling of combination therapy can describe the effects of each antibiotic against multiple bacterial populations. Our aim was to develop an efficient experimental and modeling strategy that evaluates different synergy mechanisms using a rapidly killing peptide antibiotic (nisin) combined with amikacin or linezolid as probe drugs. Serial viable counts over 48 h were obtained in time-kill experiments with all three antibiotics in monotherapy against a methicillin-resistant Staphylococcus aureus USA300 strain (inoculum, 10(8) CFU/ml). A sequential design (initial dosing of 8 or 32 mg/liter nisin, switched to amikacin or linezolid at 1.5 h) assessed the rate of killing by amikacin and linezolid against nisin-intermediate and nisin-resistant populations. Simultaneous combinations were additionally studied and all viable count profiles comodeled in S-ADAPT and NONMEM. A mechanism-based model with six populations (three for nisin times two for amikacin) yielded unbiased and precise (r = 0.99, slope = 1.00; S-ADAPT) individual fits. The second-order killing rate constants for nisin against the three populations were 5.67, 0.0664, and 0.00691 liter/(mg · h). For amikacin, the maximum killing rate constants were 10.1 h(-1) against its susceptible and 0.771 h(-1) against its less-susceptible populations, with 14.7 mg/liter amikacin causing half-maximal killing. After incorporating the effects of nisin and amikacin against each population, no additional synergy function was needed. Linezolid inhibited successful bacterial replication but did not efficiently kill populations less susceptible to nisin. Nisin plus amikacin achieved subpopulation synergy. The proposed sequential and simultaneous dosing design offers an efficient approach to quantitatively characterize antibiotic synergy over time and prospectively evaluate antibiotic combination dosing strategies.

| S-EPMC3632905 | biostudies-other

New Frontiers in Prostate Cancer Treatment: Are We Ready for Drug Combinations with Novel Agents?

Project description:Medical treatment for metastatic castration-resistant prostate cancer (mCRPC) patients has progressively been evolving from a nonspecific clinical approach to genomics-oriented therapies. The scientific community is in fact increasingly focusing on developing DNA damage repair (DDR) defect-driven novel molecules, both as single-agent therapy and in combined treatment strategies. Accordingly, research is under way into combined drug therapies targeting different pathways, e.g. androgen receptor signaling (ARS) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, immune checkpoint (IC) and PARP, IC, and ARS, and prostate-specific membrane antigen (PSMA). In an attempt to formulate evolving treatment paradigms in mCRPC patients, here we selected clinical research into patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors. In order to focus on those molecules and drug combinations most likely to be translated into routine clinical care in the near future, we selected only those clinical studies currently recruiting patients. A PubMed search focusing on the keywords "prostate cancer", "metastatic castration-resistant prostate cancer", "DDR pathways", "ARS inhibitors", "PARP inhibitors", "IC inhibitors", "PSMA-targeting agents", and "drug combinations" was performed.

| S-EPMC7349416 | biostudies-literature

Exploiting the DNA Damage Response for Prostate Cancer Therapy.

Project description:Prostate cancers that progress despite androgen deprivation develop into castration-resistant prostate cancer, a fatal disease with few treatment options. In this review, we discuss the current understanding of prostate cancer subtypes and alterations in the DNA damage response (DDR) that can predispose to the development of prostate cancer and affect its progression. We identify barriers to conventional treatments, such as radiotherapy, and discuss the development of new therapies, many of which target the DDR or take advantage of recurring genetic alterations in the DDR. We place this in the context of advances in understanding the genetic variation and immune landscape of CRPC that could help guide their use in future treatment strategies. Finally, we discuss several new and emerging agents that may advance the treatment of lethal disease, highlighting selected clinical trials.

| S-EPMC10777950 | biostudies-literature

Exploiting immune-dependent effects of microtubule-targeting agents to improve efficacy and tolerability of cancer treatment.

Project description:Microtubule-targeting agents (MTAs), like taxanes and vinca alkaloids, are tubulin-binding drugs that are very effective in the treatment of various types of cancers. In cell cultures, these drugs appear to affect assembly of the mitotic spindle and to delay progression through mitosis and this correlates with their ability to induce cell death. Their clinical efficacy is, however, limited by resistance and toxicity. For these reasons, other spindle-targeting drugs, affecting proteins such as certain kinesins like Eg5 and CENP-E, or kinases like Plk1, Aurora A and B, have been developed as an alternative to MTAs. However, these attempts have disappointed in the clinic since these drugs show poor anticancer activity and toxicity ahead of positive effects. In addition, whether efficacy of MTAs in cancer treatment is solely due to their ability to delay mitosis progression remains controversial. Here we discuss recent findings indicating that the taxane paclitaxel can promote a proinflammatory response by activation of innate immunity. We further describe how this can help adaptive antitumor immune response and suggest, on this basis and on the recent success of immune checkpoint inhibitors in cancer treatment, that a combination therapy based on low doses of taxanes and immune checkpoint inhibitors may be of high clinical advantage in terms of wide applicability, reduced toxicity, and increased antitumor response.

| S-EPMC7217828 | biostudies-literature

Exploiting epigenetic targets to overcome taxane resistance in prostate cancer.

Project description:The development of taxane resistance remains a major challenge for castration resistant prostate cancer (CR-PCa), despite the effectiveness of taxanes in prolonging patient survival. To uncover novel targets, we performed an epigenetic drug screen on taxane (docetaxel and cabazitaxel) resistant CR-PCa cells. We identified BRPF reader proteins, along with several epigenetic groups (CBP/p300, Menin-MLL, PRMT5 and SIRT1) that act as targets effectively reversing the resistance mediated by ABCB1. Targeting BRPFs specifically resulted in the resensitization of resistant cells, while no such effect was observed on the sensitive compartment. These cells were successfully arrested at the G2/M phase of cell cycle and underwent apoptosis upon BRPF inhibition, confirming the restoration of taxane susceptibility. Pharmacological inhibition of BRPFs reduced ABCB1 activity, indicating that BRPFs may be involved in an efflux-related mechanism. Indeed, ChIP-qPCR analysis confirmed binding of BRPF1 to the ABCB1 promoter suggesting direct regulation of the ABCB1 gene at the transcriptional level. RNA-seq analysis revealed that BRPF1 knockdown affects the genes enriched in mTORC1 and UPR signaling pathways, revealing potential mechanisms underlying its functional impact, which is further supported by the enhancement of taxane response through the combined inhibition of ABCB1 and mTOR pathways, providing evidence for the involvement of multiple BRPF1-regulated pathways. Beyond clinical attributes (Gleason score, tumor stage, therapy outcome, recurrence), metastatic PCa databases further supported the significance of BRPF1 in taxane resistance, as evidenced by its upregulation in taxane-exposed PCa patients.

| S-EPMC10861560 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data