Targeting cancer metabolism through synthetic lethality-based combinatorial treatment strategies

The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

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Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications

Biomedicines ◽

10.3390/biomedicines9060607 ◽

2021 ◽

Vol 9 (6) ◽

pp. 607

Author(s):

Alice Indini ◽

Francesco Grossi ◽

Mario Mandalà ◽

Daniela Taverna ◽

Valentina Audrito

Keyword(s):

Metabolic Pathways ◽

Cancer Metabolism ◽

Acquired Resistance ◽

Treatment Strategies ◽

Predictive Biomarkers ◽

Treatment Resistance ◽

Metastatic Potential ◽

Biological Behavior ◽

Therapeutic Implications ◽

Systemic Treatments

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.

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An in-silico approach to predict and exploit synthetic lethality in cancer metabolism

Nature Communications ◽

10.1038/s41467-017-00555-y ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 20

Author(s):

Iñigo Apaolaza ◽

Edurne San José-Eneriz ◽

Luis Tobalina ◽

Estíbaliz Miranda ◽

Leire Garate ◽

...

Keyword(s):

In Silico ◽

Cancer Metabolism ◽

Synthetic Lethality

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A network-based approach to integrate nutrient environment in the prediction of synthetic lethality in cancer metabolism

10.1101/2021.09.01.458495 ◽

2021 ◽

Author(s):

Iñigo Apaolaza ◽

Edurne San José-Enériz ◽

Luis Valcarcel ◽

Xabier Agirre ◽

Felipe Prosper ◽

...

Keyword(s):

Cancer Metabolism ◽

Synthetic Lethality ◽

Experimental Proof ◽

Synthetic Lethal ◽

New Family ◽

Novel Approach ◽

Synthetic Lethal Interactions ◽

Nutrient Environment ◽

Tumor Environment ◽

Definition Of

Synthetic Lethality (SL) is a promising concept in cancer research. A number of computational methods have been developed to predict SL in cancer metabolism, among which our network-based computational approach, based on genetic Minimal Cut Sets (gMCSs), can be found. A major challenge of these approaches to SL is to systematically consider tumor environment, which is particularly relevant in cancer metabolism. Here, we propose a novel definition of SL for cancer metabolism that integrates genetic interactions and nutrient availability in the environment. We extend our gMCSs approach to determine this new family of metabolic synthetic lethal interactions. A computational and experimental proof-of-concept is presented for predicting the lethality of dihydrofolate reductase inhibition in different environments. Finally, our novel approach is applied to identify extracellular nutrient dependences of tumor cells, elucidating cholesterol and myo-inositol depletion as potential vulnerabilities in different malignancies.

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Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer

Cancers ◽

10.3390/cancers13164235 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4235

Author(s):

Anna Maxi Wandmacher ◽

Anne Letsch ◽

Susanne Sebens

Keyword(s):

Clinical Trials ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Published Data ◽

Full Potential ◽

Treatment Approaches ◽

Treatment Regimens ◽

Combinatorial Treatment

To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC.

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Addition of Multimodal Immunotherapy to Combination Treatment Strategies for Children with DIPG: A Single Institution Experience

Medicines ◽

10.3390/medicines7050029 ◽

2020 ◽

Vol 7 (5) ◽

pp. 29 ◽

Cited By ~ 2

Author(s):

Stefaan Van Gool ◽

Jennifer Makalowski ◽

Erin Bonner ◽

Oliver Feyen ◽

Matthias Domogalla ◽

...

Keyword(s):

Multimodal Therapy ◽

Treatment Approach ◽

Treatment Strategies ◽

Primary Treatment ◽

Diffuse Intrinsic Pontine Glioma ◽

Compassionate Use ◽

Single Institution ◽

Major Toxicity ◽

Dendritic Cell Vaccines ◽

Combinatorial Treatment

Background: The prognosis of children with diffuse intrinsic pontine glioma (DIPG) remains dismal despite radio- and chemotherapy or molecular-targeted therapy. Immunotherapy is a powerful and promising approach for improving the overall survival (OS) of children with DIPG. Methods: A retrospective analysis for feasibility, immune responsiveness, and OS was performed on 41 children treated in compassionate use with multimodal therapy consisting of Newcastle disease virus, hyperthermia, and autologous dendritic cell vaccines as part of an individualized combinatorial treatment approach for DIPG patients. Results: Patients were treated at diagnosis (n = 28) or at the time of progression (n = 13). In the case of 16 patients, histone H3K27M mutation was confirmed by analysis of biopsy (n = 9) or liquid biopsy (n = 9) specimens. PDL1 mRNA expression was detected in circulating tumor cells of ten patients at diagnosis. Multimodal immunotherapy was feasible as scheduled, until progression, in all patients without major toxicity. When immunotherapy was part of primary treatment, median PFS and OS were 8.4 m and 14.4 m from the time of diagnosis, respectively, with a 2-year OS of 10.7%. When immunotherapy was given at the time of progression, median PFS and OS were 6.5 m and 9.1 m, respectively. A longer OS was associated with a Th1 shift and rise in PanTum Detect test scores. Conclusions: Multimodal immunotherapy is feasible without major toxicity, and warrants further investigation as part of a combinatorial treatment approach for children diagnosed with DIPG.

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Defining the landscape of metabolic dysregulations in cancer metastasis

Clinical & Experimental Metastasis ◽

10.1007/s10585-021-10140-9 ◽

2021 ◽

Author(s):

Sara Abdul Kader ◽

Shaima Dib ◽

Iman W. Achkar ◽

Gaurav Thareja ◽

Karsten Suhre ◽

...

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Cell Lines ◽

Cancer Metabolism ◽

Treatment Strategies ◽

Metastatic Potential ◽

Breast Cancer Cell Lines ◽

Growth Media ◽

High Metastatic Potential ◽

Tnbc Cell

AbstractMetastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies. However, the metabolic signatures of metastatic cells remain vastly elusive. Our aim was to determine metabolic dysregulations associated with high metastatic potential in breast cancer cell lines. We have selected 5 triple negative breast cancer (TNBC) cell lines including three with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and two with low metastatic potential (LMP) (BT549, HCC1143). The normal epithelial breast cell line (hTERT-HME1) was also investigated. The untargeted metabolic profiling of cells and growth media was conducted and total of 479 metabolites were quantified. First we characterized metabolic features differentiating TNBC cell lines from normal cells as well as identified cell line specific metabolic fingerprints. Next, we determined 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.

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Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas

Science Advances ◽

10.1126/sciadv.aaz3221 ◽

2020 ◽

Vol 6 (17) ◽

pp. eaaz3221 ◽

Cited By ~ 6

Author(s):

Yuxiang Wang ◽

Aaron T. Wild ◽

Sevin Turcan ◽

Wei H. Wu ◽

Carlie Sigel ◽

...

Keyword(s):

Dna Damage ◽

Synthetic Lethality ◽

Treatment Strategies ◽

Parp Inhibition ◽

Global Changes ◽

Therapeutic Effects ◽

Multiple Cancer ◽

Idh Mutations ◽

Preclinical Animal Models

Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5′-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.

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Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids

Cell Death and Disease ◽

10.1038/s41419-021-03572-4 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Martina Lepore Signorile ◽

Valentina Grossi ◽

Simone Di Franco ◽

Giovanna Forte ◽

Vittoria Disciglio ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Kinase Inhibitor ◽

Synthetic Lethality ◽

Locally Advanced ◽

Treatment Strategies ◽

Chemotherapeutic Agents ◽

Model Systems ◽

Metastatic Dissemination

AbstractThe prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.

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