Purpose: HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TGs) that ~50% of clear cell renal cell carcinomas (ccRCCs) are HIF2α dependent. However, prolonged treatment induced resistance mutations, which we also identified in humans. Here, we evaluated a tumor-directed, systemically-delivered, siRNA drug (siHIF2) active against wild-type and resistant mutant HIF2α. Experimental Design: Using our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation and anti-tumor activity. Orthogonal RNA-seq studies of siHIF2 and PT2399 were pursued to define the HIF2 transcriptome. Analyses were extended to a TG line generated from a study biopsy of a siHIF2 phase I clinical trial (NCT04169711) participant and the corresponding patient, an extensively pretreated individual with rapidly progressive ccRCC and paraneoplastic polycythemia likely evidencing a HIF2 dependency. Results: siHIF2 was taken up by ccRCC TGs, effectively depleted HIF2α, deactivated orthogonally-defined effector pathways (including Myc and novel E2F pathways), downregulated cell cycle genes and inhibited tumor growth. Effects on the study subject TG paralleled those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed obviating the need for phlebotomies, and a partial response was induced. Conclusions: To our knowledge, this is the first example of functional inactivation of an oncoprotein and tumor suppression with a systemic, tumor-directed, RNA-silencing drug. These studies provide a proof-of-principle of HIF2α inhibition by RNA-targeting drugs in ccRCC and establish a paradigm for tumor-directed RNA-based therapeutics in cancer.
The role of Trichoderma harzianum, Bacillus subtilis and Pseudomonas fluorescens (alone and in combination) in inducing systemic resistance in chickpea exposed to Fusarium oxysporum ciceris was investigated. Chickpea seed (var. Radhey) treatment with Trichoderma harzianum, Bacillus subtilis and Pseudomonas fluorescens alone and in combination on the germination, wilt incidence, plant growth promotion, yield, production of chlorophyll, protein, peroxidase, polyphenol oxidase and total phenol content was recorded. The results of in vitro studies revealed better performances of treatment T6 (Seed treatment with 1% Trichoderma harzianum + 2% Pseudomonas fluorescens + 2% Bacillus subtilis in combination). This treatment significantly reduced wilt incidence and increased germination, root length, shoot length, and yield as compared to untreated control. Treatment T6 also induced 1.4 per cent increase in peroxidase, 1.6 in polyphenol oxidase and 2.3 in total phenol in chickpea during pathogenesis by F. oxysporum ciceris f. sp. Similarly, 1.9% increase in chlorophyll and protein was recorded with the treatment T6 as compared to control. Present investigations will be helpful in formulating novel bioformulations using fungal and bacterial bioagents to control wilt in chickpea.
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