HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans
HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell carcinomas (ccRCC) are HIF2α dependent. However, prolonged treatment induced resistance mutations, which we also identified in humans. Here, we ev...
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| Vydáno v: | Clinical cancer research Ročník 28; číslo 24; s. 5405 |
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15.12.2022
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| ISSN: | 1557-3265, 1557-3265 |
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| Abstract | HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell carcinomas (ccRCC) 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.
Using our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation, and antitumor activity. Orthogonal RNA-sequencing 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.
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 mimicked those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed, and a partial response was induced.
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. |
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| AbstractList | HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell carcinomas (ccRCC) 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.
Using our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation, and antitumor activity. Orthogonal RNA-sequencing 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.
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 mimicked those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed, and a partial response was induced.
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. HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell carcinomas (ccRCC) 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.PURPOSEHIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell carcinomas (ccRCC) 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.Using our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation, and antitumor activity. Orthogonal RNA-sequencing 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.EXPERIMENTAL DESIGNUsing our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation, and antitumor activity. Orthogonal RNA-sequencing 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.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 mimicked those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed, and a partial response was induced.RESULTSsiHIF2 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 mimicked those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed, and a partial response was induced.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.CONCLUSIONSTo 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. |
| Author | Christie, Alana Wong, So C Carrillo, Deyssy Schluep, Thomas Brugarolas, James Fatunde, Oluwatomilade Mishra, Akhilesh Macchiaroli, Alyssa Onabolu, Oreoluwa Woolford, Layton Do, Quyen N Hamilton, James Joyce, Allison Hardy, Tanner He, Wei Saatchi, Faeze Stevens, Christina Toffessi Tcheuyap, Vanina Miyata, Jeffrey Kanner, Steven B McKenzie, Tiffani Kapur, Payal Ma, Yuanqing Brandenburg, Olivia Pedrosa, Ivan Ivanishev, Alexander Yousuf, Qurratulain Zhang, Qing Li, Daniel |
| Author_xml | – sequence: 1 givenname: Yuanqing orcidid: 0000-0002-6637-4414 surname: Ma fullname: Ma, Yuanqing organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 2 givenname: Allison orcidid: 0000-0001-6127-4724 surname: Joyce fullname: Joyce, Allison organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 3 givenname: Olivia orcidid: 0000-0002-9832-2002 surname: Brandenburg fullname: Brandenburg, Olivia organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 4 givenname: Faeze orcidid: 0000-0001-9151-7133 surname: Saatchi fullname: Saatchi, Faeze organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 5 givenname: Christina orcidid: 0000-0003-2642-738X surname: Stevens fullname: Stevens, Christina organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 6 givenname: Vanina orcidid: 0000-0002-6817-9241 surname: Toffessi Tcheuyap fullname: Toffessi Tcheuyap, Vanina organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 7 givenname: Alana orcidid: 0000-0002-7034-818X surname: Christie fullname: Christie, Alana organization: O'Donnell School of Public Health, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 8 givenname: Quyen N orcidid: 0000-0001-9511-7866 surname: Do fullname: Do, Quyen N organization: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 9 givenname: Oluwatomilade orcidid: 0000-0001-5776-1968 surname: Fatunde fullname: Fatunde, Oluwatomilade organization: Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 10 givenname: Alyssa orcidid: 0000-0003-2333-8015 surname: Macchiaroli fullname: Macchiaroli, Alyssa organization: Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 11 givenname: So C orcidid: 0000-0002-9070-9587 surname: Wong fullname: Wong, So C organization: Arrowhead Pharmaceuticals, Pasadena, California – sequence: 12 givenname: Layton orcidid: 0000-0001-7116-6233 surname: Woolford fullname: Woolford, Layton organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 13 givenname: Qurratulain orcidid: 0000-0002-6257-2536 surname: Yousuf fullname: Yousuf, Qurratulain organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 14 givenname: Jeffrey orcidid: 0000-0001-8278-3026 surname: Miyata fullname: Miyata, Jeffrey organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 15 givenname: Deyssy orcidid: 0000-0002-5836-9084 surname: Carrillo fullname: Carrillo, Deyssy organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 16 givenname: Oreoluwa orcidid: 0000-0003-2790-8118 surname: Onabolu fullname: Onabolu, Oreoluwa organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 17 givenname: Tiffani orcidid: 0000-0001-8518-0538 surname: McKenzie fullname: McKenzie, Tiffani organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 18 givenname: Akhilesh orcidid: 0000-0002-0185-5022 surname: Mishra fullname: Mishra, Akhilesh organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 19 givenname: Tanner orcidid: 0000-0002-2969-0944 surname: Hardy fullname: Hardy, Tanner organization: Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 20 givenname: Wei orcidid: 0000-0002-4272-2891 surname: He fullname: He, Wei organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 21 givenname: Daniel orcidid: 0000-0002-1530-8310 surname: Li fullname: Li, Daniel organization: Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 22 givenname: Alexander orcidid: 0000-0003-0971-9567 surname: Ivanishev fullname: Ivanishev, Alexander organization: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 23 givenname: Qing orcidid: 0000-0002-6595-8995 surname: Zhang fullname: Zhang, Qing organization: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 24 givenname: Ivan orcidid: 0000-0002-0371-8689 surname: Pedrosa fullname: Pedrosa, Ivan organization: Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 25 givenname: Payal orcidid: 0000-0002-4239-0495 surname: Kapur fullname: Kapur, Payal organization: Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas – sequence: 26 givenname: Thomas orcidid: 0000-0002-2986-7287 surname: Schluep fullname: Schluep, Thomas organization: Arrowhead Pharmaceuticals, Pasadena, California – sequence: 27 givenname: Steven B orcidid: 0000-0002-7698-9113 surname: Kanner fullname: Kanner, Steven B organization: Arrowhead Pharmaceuticals, Pasadena, California – sequence: 28 givenname: James orcidid: 0000-0002-5494-2744 surname: Hamilton fullname: Hamilton, James organization: Arrowhead Pharmaceuticals, Pasadena, California – sequence: 29 givenname: James orcidid: 0000-0002-8575-499X surname: Brugarolas fullname: Brugarolas, James organization: Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas |
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| Snippet | HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell... |
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| SubjectTerms | Animals Basic Helix-Loop-Helix Transcription Factors - metabolism Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - pathology Cell Line, Tumor Clinical Trials, Phase I as Topic Humans Kidney Neoplasms - drug therapy Kidney Neoplasms - genetics Kidney Neoplasms - pathology Mice Polycythemia RNA, Small Interfering - genetics |
| Title | HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans |
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