The Quest for an Effective Treatment for an Intractable Cancer

Quinn, Bridget A.; Lee, Nathaniel A.; Kegelman, Timothy P.; Bhoopathi, Praveen; Emdad, Luni; Das, Swadesh K.; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B.

doi:10.1016/bs.acr.2015.04.009

Cited by 11 publications

(4 citation statements)

References 58 publications

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“…However, there are still subsets of patients across all malignancies that fail to respond to these therapies. In specific malignancy types, such as CRPC (47,48) and pancreatic ductal adenocarcinoma (49), very few responses to these T cell checkpoint blockade therapies have been reported, highlighting a strong unmet need for investigating combination therapies to improve clinical responses to CTLA-4 and/or PD-1/PD-L1 blockade. The combination of cabozantinib with approaches that activate adaptive immunity, such as T-cell checkpoint blockade or vaccine-based approaches may provide durable benefit in advanced cancer patients and warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity

et al. 2017

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Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor, plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anti-cancer innate immune response, resulting in tumor clearance.

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Section: Discussionmentioning

confidence: 99%

Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity

et al. 2017

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“…Aberrant EphA2 overexpression causes an excess of unbound receptor and it contributes to the spread of certain solid tumors including prostate cancer [ 1 , 17 ], melanoma [ 13 , 18 ], breast cancer [ 2 , 3 ], brain cancer [ 10 , 19 ], ovarian cancer [ 20 ], urinary bladder cancer [ 11 ], pancreatic cancer [ 5 , 6 , 21 , 22 ], esophageal cancer [ 23 ], lung cancer [ 24 ], stomach cancer [ 25 ], and several types of leukemia [ 15 , 16 ]. In pancreatic cancer, an extremely aggressive tumor which accounts for about 7% of all cancer deaths in the United States, EphA2 overexpression is inversely correlated with patient survival [ 5 , 21 ]. More recent studies underlined the role of EphA2 in driving therapy-resistant pancreatic adenocarcinomas, suggesting that EphA2-targeting agents should be developed and used in combination with current therapeutics [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Effective Tumor Targeting by EphA2-Agonist-Biotin-Streptavidin Conjugates

et al. 2021

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We recently reported on a potent synthetic agent, 135H11, that selectively targets the receptor tyrosine kinase, EphA2. While 135H11 possesses a relatively high binding affinity for the ligand-binding domain of EphA2 (Kd~130 nM), receptor activation in the cell required the synthesis of dimeric versions of such agent (namely 135H12). This was expected given that the natural ephrin ligands also need to be dimerized or clustered to elicit agonistic activity in cell. In the present report we investigated whether the agonistic activity of 135H11 could be enhanced by biotin conjugation followed by complex formation with streptavidin. Therefore, we measured the agonistic EphA2 activity of 135H11-biotin (147B5) at various agent/streptavidin ratios, side by side with 135H12, and a scrambled version of 147B5 in pancreatic- and breast-cancer cell lines. The (147B5)n-streptavidin complexes (when n = 2, 3, 4, but not when n = 1) induced a strong receptor degradation effect in both cell lines compared to 135H12 or the (scrambled-147B5)4-streptavidin complex as a control, indicating that multimerization of the targeting agent resulted in an increased ability to cause receptor clustering and internalization. Subsequently, we prepared an Alexa-Fluor-streptavidin conjugate to demonstrate that (147B5)4-AF-streptavidin, but not the scrambled equivalent complex, concentrates in pancreatic and breast cancers in orthotopic nude-mouse models. Hence, we conclude that these novel targeting agents, with proper derivatization with imaging reagents or chemotherapy, can be used as diagnostics, and/or to deliver chemotherapy selectively to EphA2-expressing tumors.

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“…Most tumors are either locally advanced or have metastasized at the time of diagnosis and, intrinsically, this cancer is extremely resistant to chemotherapy and radiation. Currently, first line treatment for pancreatic cancer consists of surgical resection, if possible, and a subsequent course of chemotherapy [ 1 ]. This chemotherapy usually consists of treatment with Gemcitabine [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine

et al. 2016

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First line treatment for pancreatic cancer consists of surgical resection, if possible, and a subsequent course of chemotherapy using the nucleoside analogue gemcitabine. In some patients, an active transport mechanism allows gemcitabine to enter efficiently into the tumor cells, resulting in a significant clinical benefit. However, in most patients, low expression of gemcitabine transporters limits the efficacy of the drug to marginal levels, and patients need frequent administration of the drug at high doses, significantly increasing systemic drug toxicity. In this article we focus on a novel targeted delivery approach for gemcitabine consisting of conjugating the drug with an EphA2 targeting agent. We show that the EphA2 receptor is highly expressed in pancreatic cancers, and accordingly, the drug-conjugate is more effective than gemcitabine alone in targeting pancreatic tumors. Our preliminary observations suggest that this approach may provide a general benefit to pancreatic cancer patients and offers a comprehensive strategy for enhancing delivery of diverse therapeutic agents to a wide range of cancers overexpressing EphA2, thereby potentially reducing toxicity while enhancing therapeutic efficacy.

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The Quest for an Effective Treatment for an Intractable Cancer

Cited by 11 publications

References 58 publications

Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity

Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity

Effective Tumor Targeting by EphA2-Agonist-Biotin-Streptavidin Conjugates

Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine

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