scholarly journals OMRT-7. Angiogenesis inhibitors strongly synergize with therapeutics targeting tumor metabolism

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Sunada Khadka
Keyword(s):  
Kinase Inhibitor ◽  
Metabolic Stress ◽  
Angiogenesis Inhibitors ◽  
Tumor Metabolism ◽  
Nutrient Stress ◽  
Full Potential ◽  
Cancer Therapies ◽  
Angiogenesis Inhibition ◽  
Cancer Cell Death ◽  
Amino Acid Depletion

Abstract Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their death. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit some degree of metabolic stress, this is stress is not sufficient to induce significant cancer cell death. We posit that the full potential of angiogenesis inhibition can be realized by the combination of angiogenesis inhibition with emerging tumor metabolism targeting therapies. Because tumors under angiogenesis inhibition are already in a state of nutrient stress, the effects of metabolically targeted therapies such as amino acid depletion (e.g. asparginase, methionine restriction), inhibitors of stress adaption (AMPK and GCN2 inhibitors) or energy metabolism (e.g. IACS-010759, Metformin, POMHEX) stand to dramatically increase in potency whilst remaining selective for (angiogenic) tumor versus (non-angiogenic) normal tissue. Here, we provide proof-of-principal for this thesis. First, we performed metabolomic profiling of angiogenesis-inhibited tumors, which corroborates a state of nutrient stress in angiogenesis-inhibited tumors. Second, we demonstrate dramatic anti-neoplastic synergy (effectively curing of xenografted tumor-bearing mice, irrespective of initial tumor size), without enhanced adverse toxicities, between the OxPhos inhibitor IACS-010759 and the angiogenesis tyrosine kinase inhibitor, Tivozanib. The same results were recapitulated with the anti-VEGFA antibody, Avastin, and the OxPhos inhibitor could be substituted with the Enolase inhibitor HEX, with similar effects. The synergy was observed in a broad range of tumor types, even those without clear genetic susceptibilities. Together, these results suggest that angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.

scholarly journals TAMI-62. ANGIOGENESIS INHIBITORS STRONGLY SYNERGIZE WITH THERAPEUTICS TARGETING TUMOR METABOLISM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii227-ii227
Author(s):  
Sunada Khadka ◽  
Yu-Hsi Lin ◽  
Jeffrey Ackroyd ◽  
Kenisha Arthur ◽  
Yasaman Barekatain ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Metabolic Stress ◽  
Angiogenesis Inhibitors ◽  
Tumor Metabolism ◽  
Nutrient Stress ◽  
Full Potential ◽  
Cancer Therapies ◽  
Angiogenesis Inhibition ◽  
Cancer Cell Death ◽  
Amino Acid Depletion

Abstract Angiogenesis inhibition has become a mainstay of oncology despite having fallen short of its early promise. As originally envisioned, angiogenesis inhibition would cut off the blood supply, deprive tumor cells of key nutrients, leading to their demise. In practice, while there is evidence that tumors under angiogenesis treatment do in fact exhibit some degree of metabolic stress, this is stress is not sufficient to induce significant cancer cell death. We posit that the full potential of angiogenesis inhibition can be realized by the combination of angiogenesis inhibition with emerging tumor metabolism targeting therapies. Because tumors under angiogenesis inhibition are already in a state of nutrient stress, the effects of metabolically targeted therapies such as amino acid depletion (e.g. asparginase, methionine restriction), inhibitors of stress adaption (AMPK and GCN2 inhibitors) or energy metabolism (e.g. IACS-010759, Metformin, POMHEX) stand to dramatically increase in potency whilst remaining selective for (angiogenic) tumor versus (non-angiogenic) normal tissue. Here, we provide proof-of-principal for this thesis. First, we performed metabolomic profiling of angiogenesis-inhibited tumors, which corroborates as state of nutrient stress in angiogenesis-inhibited tumors. Second, we demonstrate dramatic anti-neoplastic synergy (effectively curing of xenografted tumor-bearing mice, irrespective of initial tumor size), without enhanced adverse toxicities, between the OxPhos inhibitor IACS-010759 and the angiogenesis tyrosine kinase inhibitor, Tivozanib. The same results were recapitulated with the anti-VEGFA antibody, Avastin, and the OxPhos inhibitor could be substituted with the Enolase inhibitor HEX, with similar effects. The synergy was observed in a broad range of tumor types, even those without clear genetic susceptibilities. Together, these results suggest that Angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.

scholarly journals Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary

2021 ◽  
Vol 22 (3) ◽  
pp. 1395
Author(s):  
Luca Mattiello ◽  
Giulia Pucci ◽  
Francesco Marchetti ◽  
Marc Diederich ◽  
Stefania Gonfloni
Keyword(s):  
Ovarian Reserve ◽  
Kinase Inhibitor ◽  
Concomitant Administration ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Abl Tyrosine Kinase ◽  
Negative Impacts ◽  
Abl Tyrosine Kinase Inhibitor

Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signaling pathways activated by cyclophosphamide in mouse ovaries. We also provide evidence that Asciminib does not interfere with the cytotoxic effect of cyclophosphamide in Michigan Cancer Foundation (MCF)7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide. Taken together, these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effects of cancer therapies.

scholarly journals Protein kinase inhibitor-based cancer therapies: Considering the potential of nitric oxide (NO) to improve cancer treatment

2020 ◽  
Vol 176 ◽  
pp. 113855 ◽  
Author(s):  
Silvia Ghione ◽  
Nesrine Mabrouk ◽  
Catherine Paul ◽  
Ali Bettaieb ◽  
Stéphanie Plenchette
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Cancer Treatment ◽  
Kinase Inhibitor ◽  
Protein Kinase Inhibitor ◽  
Cancer Therapies

scholarly journals Evaluate the response of Apoptosis, Angiogenesis and Cancer Therapies

2018 ◽  
Vol 2 (1) ◽  
pp. 01-08
Author(s):  
Chathura Gayan
Keyword(s):  
Fas Ligand ◽  
Vascular Endothelial Cells ◽  
Pigment Epithelium ◽  
Angiogenesis Inhibitors ◽  
Cancer Therapies ◽  
Vascular Endothelial ◽  
Pigment Epithelium Derived Factor ◽  
Distinct Cell ◽  
Traditional Therapies ◽  
Endothelial Growth Factor

Angiogenesis, the growth of new blood vessels from the existing vasculature, and is maintained in adult tissues by the balanced presence of both angiogenic inducers and inhibitors in the tissue milieu. When inducers predominate, vascular endothelial cells (VECs) become activated and in this activated VECs, distinct cell signaling pathways are initiated providing the specificity of anti-angiogenic therapies to the tumor vasculature. VEC apoptosis has been well documented in regressing vessels, and it has been shown that, in addition to activating the VECs, some inducers such as vascular endothelial growth factor also up-regulate Fas expression, thus sensitizing the cell to apoptotic stimuli. Endogenous angiogenesis inhibitors, such as thrombospondin-1(TSP-1) and pigment epithelium-derived factor (PEDF), stimulate signaling cascades within the VECs and also induce the expression of Fas ligand in activated VECs. Therefore, when inhibitors predominate, the apoptotic cascade is initiated ,thus anti-angiogenic therapies can target the inducer supply or directly target the VECs. Although clinical studies suggest that anti-angiogenic therapies may prove to be most effective when used in combination with traditional therapies

scholarly journals Cancer—A Major Cardiac Comorbidity With Implications on Cardiovascular Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel Finke ◽  
Markus B. Heckmann ◽  
Norbert Frey ◽  
Lorenz H. Lehmann
Keyword(s):  
Heart Failure ◽  
Inflammatory Cytokines ◽  
Cancer Biology ◽  
Systemic Disease ◽  
Angiogenesis Inhibitors ◽  
Acid Oxidation ◽  
Cancer Therapies ◽  
Mortality And Morbidity ◽  
Tnf Α ◽  
Preclinical And Clinical Studies

Cardiovascular diseases have multifactorial causes. Classical cardiovascular risk factors, such as arterial hypertension, smoking, hyperlipidemia, and diabetes associate with the development of vascular stenoses and coronary heart disease. Further comorbidities and its impact on cardiovascular metabolism have gotten more attention recently. Thus, also cancer biology may affect the heart, apart from cardiotoxic side effects of chemotherapies. Cancer is a systemic disease which primarily leads to metabolic alterations within the tumor. An emerging number of preclinical and clinical studies focuses on the interaction between cancer and a maladaptive crosstalk to the heart. Cachexia and sarcopenia can have dramatic consequences for many organ functions, including cardiac wasting and heart failure. These complications significantly increase mortality and morbidity of heart failure and cancer patients. There are concurrent metabolic changes in fatty acid oxidation (FAO) and glucose utilization in heart failure as well as in cancer, involving central molecular regulators, such as PGC-1α. Further, specific inflammatory cytokines (IL-1β, IL-6, TNF-α, INF-β), non-inflammatory cytokines (myostatin, SerpinA3, Ataxin-10) and circulating metabolites (D2-HG) may mediate a direct and maladaptive crosstalk of both diseases. Additionally, cancer therapies, such as anthracyclines and angiogenesis inhibitors target common metabolic mechanisms in cardiomyocytes and malignant cells. This review focuses on cardiovascular, cancerous, and cancer therapy-associated alterations on the systemic and cardiac metabolic state.

scholarly journals Siah2 control of T-regulatory cells limits anti-tumor immunity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Marzia Scortegagna ◽  
Kathryn Hockemeyer ◽  
Igor Dolgalev ◽  
Joanna Poźniak ◽  
Florian Rambow ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Cell Cycle Progression ◽  
T Regulatory Cells ◽  
Kinase Inhibitor ◽  
G1 Arrest ◽  
Cancer Therapies ◽  
Activated T Cells ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Elevated Expression

AbstractUnderstanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here, we report that growth of BRAF-mutant melanoma cells is inhibited, up to complete rejection, in Siah2−/− mice. Growth-inhibited tumors exhibit increased numbers of intra-tumoral activated T cells and decreased expression of Ccl17,Ccl22, and Foxp3. Marked reduction in Treg proliferation and tumor infiltration coincide with G1 arrest in tumor infiltrated Siah2−/− Tregs in vivo or following T cell stimulation in culture, attributed to elevated expression of the cyclin-dependent kinase inhibitor p27, a Siah2 substrate. Growth of anti-PD-1 therapy resistant melanoma is effectively inhibited in Siah2−/− mice subjected to PD-1 blockade, indicating synergy between PD-1 blockade and Siah2 loss. Low SIAH2 and FOXP3 expression is identified in immune responsive human melanoma tumors. Overall, Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and Siah2 loss in the host sensitizes melanoma to anti-PD-1 therapy.

scholarly journals Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Colin W. Garvie ◽  
Xiaoyun Wu ◽  
Malvina Papanastasiou ◽  
Sooncheol Lee ◽  
James Fuller ◽  
...  
Keyword(s):  
Cell Death ◽  
Complex Formation ◽  
Cancer Cells ◽  
Active Site ◽  
Alpha Helix ◽  
Rnase Activity ◽  
Cancer Therapies ◽  
Cancer Cell Death ◽  
New Cancer Therapies ◽  
Related Compounds

AbstractDNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.

Abstract 05: Cyclooxygenase-2 Inhibition As A New Tool To Combat Angiogenesis Inhibitor-induced Hypertension And Renal Toxicity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daan C van Dorst ◽  
Katrina M Mirabito Colafella ◽  
Leni van Doorn ◽  
Richard van Veghel ◽  
Ingrid M Garrelds ◽  
...  
Keyword(s):  
Vascular Function ◽  
Renal Toxicity ◽  
Angiogenesis Inhibitor ◽  
Angiogenesis Inhibitors ◽  
High Dose ◽  
Angiogenesis Inhibition ◽  
Dose Aspirin ◽  
Induced Hypertension ◽  
Cox 2 ◽  
Cox 1

Angiogenesis inhibitors are effective anti-cancer agents, but also cause hypertension and renal injury. Earlier, we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and -2) prevented these side effects better than low-dose aspirin (blocking COX-1 only). Therefore, we hypothesized that selective COX-2 inhibition would prevent toxicity during angiogenesis inhibition, and that this toxicity involves a reduced ratio of vasodilator/constrictor COX-derived prostanoids, i.e., prostacyclin (PGI 2 ) and thromboxane (TXA 2 ). Male WKY rats received vehicle, angiogenesis inhibition (sunitinib (SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10mg/kg/day), a PGI 2 analogue (iloprost 100 μg/kg/day), or a dual TXA 2 synthase/receptor antagonist (picotamide, 2.5 mg/kg/day) for 8 days (n=7-8/group). Mean arterial pressure (MAP) was measured via radiotelemetry, vascular function was assessed via wire myography, and biochemical measurements were performed by ELISA. SU induced a rapid increase in MAP (16±2 vs. 3±1 mmHg after vehicle on day 6, P<0.001), which was blunted by celecoxib (10±2 mmHg on day 6, P=0.06 versus SU), temporarily attenuated by iloprost (on treatment days 1-2) and unaffected by picotamide. Wire myography demonstrated a trend towards increased vasoconstrictor response to endothelin-1 in iliac arteries after SU, which was prevented by celecoxib (P<0.001). SU increased albuminuria (0.6±0.1 vs. 0.3±0.1 mg/24h after vehicle; P<0.001), and this was prevented by celecoxib only (0.4±0.1 mg/24h, P=0.01 vs. SU). SU increased the PGI 2 /TXA 2 ratio in both plasma (2.7±1.2 vs. 0.6±0.2 after vehicle, P=0.05) and urine (22±2.2 vs. 0.9±0.2 after vehicle, P<0.001). In conclusion, selective COX-2 inhibition combats angiogenesis inhibitor-induced hypertension and renal toxicity. SU paradoxically increases the PGI 2 /TXA 2 ratio, particularly in the kidney. Although this upregulation might initially be protective, it could eventually contribute to renal toxicity, most likely because PGI 2 exerts deleterious effects in excessive concentrations. Targeting excessive renal PGI 2 production might be another promising strategy to prevent renal toxicity during angiogenesis inhibition.

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