<p>Supplementary Figure S1. High expression of UBA1 is associated with low levels of intratumoral CD8+ T cells and predictive of ICB resistance and poor survival in ICB cohorts.</p>
305 Background: A proportion of patients treated with anti-VEGF therapy first line exhibit progressive disease (PD) as best response (per RECIST). The characteristics and outcome of this population are poorly understood. Methods: Data from patients with mRCC treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Results: One thousand fifty-six evaluable patients were treated with VEGF-inhibitors as their first-line antiangiogenic therapy. Of those, 272 (26%) patients had PD as best response. Their initial treatment was sunitinib (n=203), sorafenib (n=51), or bevacizumab (n=18). Six percent of patients were favorable risk, 55% intermediate risk, and 39% poor risk as per Heng et al JCO 2009 prognostic factors. On multivariable analysis, predictors of PD at first restaging were KPS < 80% (OR 2.3, p < 0.0001), diagnosis to treatment < 1 year (OR 2.1, p < 0.0001), neutrophilia (OR 1.9, p = 0.0021), thrombocytosis (OR 1.7, p = 0.0068), and anemia (OR 1.6, p = 0.0058). The median progression-free survival (PFS) and overall survival (OS) in patients with primary refractory disease vs. patients without (i.e., partial response or stable disease) was 2.4 vs. 11 months (p<0.0001) and 6.8 vs. 29 months (p<0.0001), respectively. Only 108 (40%) VEGF-refractory patients proceeded to receive 2 nd line VEGF inhibitors (sunitinib (n=32), sorafenib (n=44), axitinib (n=2), bevacizumab (n=4)), mTOR inhibitors (temsirolimus (n=14), everolimus (n=11)), or interferon (n=1). The response rate, PFS and OS of this second-line therapy was 9%, 2.5 months and 7.4 months, respectively. The response rate, PFS and OS of those receiving second-line VEGF vs. mTOR inhibitors was 10% vs. 6% (p=NS), 2.8 vs. 2.0 months (p=0.069) and 7.9 vs. 4.7 months (p=0.40), respectively. Conclusions: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR agents may not be better than alternate anti-VEGF agents after primary anti-VEGF failure. Investigation into the mechanism of primary resistance and alternative therapeutic strategies are needed. [Table: see text]
Abstract The switch/sucrose non-fermentable (SWI/SNF) complex plays a crucial role in chromatin remodeling and is recurrently altered in over 20% of human cancers. Here, we developed a proteolysis targeting chimera (PROTAC) degrader of ATPase subunits of the SWI/SNF complex, SMARCA2 and SMARCA4. Intriguingly, we found androgen receptor (AR)/forkhead box A1 (FOXA1)-positive prostate cancer to be exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to benign prostate as well as other cancer cell lines, including those with inactivating SMARCA4 mutations. Mechanistically, SWI/SNF inhibition rapidly compacts the cis-regulatory elements that are bound and activated by transcription factors that drive cancer proliferation, namely AR, FOXA1, ERG, and MYC. This ensues in chromatin untethering of these oncogenic drivers, chemical decommissioning of their core enhancer circuitry, and attenuation of downstream gene programs. Furthermore, we found SWI/SNF inhibition to disrupt super-enhancer and promoter DNA looping interactions that wire supra-physiologic expression of the AR, FOXA1, and MYC oncogenes, thereby tempering their expression in cancer cells. Monotherapy with the SMARCA2/4 degrader induced potent inhibition of tumor growth in cell line-derived xenograft models of prostate cancer and remarkably synergized with AR antagonists, inducing disease remission in models of castration-resistant prostate cancer. We also found the combinatorial treatment to significantly inhibit the growth of enzalutamide resistant disease using in vitro as well as patient-derived xenograft models. Notably, no major toxicities were seen in mice upon prolonged treatment with the SMARCA2/4 degrader, including no indications of thrombocytopenia, gastrointestinal goblet cell depletion, or germ cell degeneration. Taken together, these results suggest that impeding enhancer accessibility through SWI/SNF ATPase inactivation represents a novel therapeutic approach in enhancer addicted human cancers. Citation Format: Lanbo Xiao, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa Pushpinder, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, Yu Chang, Xiaoju Wang, Yuping Zhang, Josh Vo, Steven Kregel, Stephanie A. Simko, Andrew D. Delekta, Mustapha Jaber, Heng Zheng, Ingrid Apel, Lisa McMurry, Fengyun Su, Rui Wang, Sylvia Wang, Sanjita Sasmal, Leena K. Satyam, Subhendu Mukherjee, Chandrasekhar AbbinenI, Kiran Aithal, Mital S. Bhakta, Jay Ghurye, Xuhong Cao, Nora M. Navone, Alexey Nesvizhskii, Rohit Mehra, Ulka Vaishampayan, Marco Blanchette, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra, Arul M. Chinnaiyan. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5469.
Transforming growth factor-beta 1 (TGFβ1) plays an important role in mediating the primary resistance to PD-1/PD-L1 [PD-(L)1] blockade. SRK-181 is a fully human, selective anti-latent TGFβ1 IgG4 monoclonal antibody under investigation as a monotherapy or in combination with anti-PD(L)1 therapy in patients with solid tumors. Compared to broad TGFβ inhibitors, SRK-181 was observed to have improved safety profile (no cardiotoxicities) in four-week GLP nonclinical toxicology studies.
Methods
The DRAGON trial (NCT04291079) is an ongoing open-label, phase 1 study. Part A followed a 3+3 dose escalation design to evaluate SRK-181 in patients with advanced solid tumors at 80-3000mg every three weeks (q3w) and 2000mg q2w in Part A1, and SRK-181+anti-PD-(L)1 in patients who did not respond to prior anti-PD-(L)1 therapy at 240-2400mg q3w in Part A2. In Part B (expansion phase), SRK-181 (1500mg q3w or 1000mg q2w)+anti-PD-(L)1 are administered in anti-PD-(L)1-resistant patients with non-small cell lung cancer (NSCLC), urothelial carcinoma, melanoma, clear cell renal cell carcinoma (ccRCC) or other advanced solid tumors. The level of circulatory TGFβ1 was assessed as a target engagement biomarker.
Results
As of 2 June 2022, Part A1 and Part A2 enrolled 19 and 15 patients, respectively, with median prior lines of therapies of 4 (range 1-10). No dose limiting toxicity (DLT) were observed in Part A. In Part A1, the most common treatment-related AEs (TRAEs, >10%) of any grade were fatigue (16%, n=3), decreased appetite and nausea (each: 11%, n=2). Eight patients had stable disease (SD) as best response (3/colorectal, 3/ovarian, 1/pancreatic, and 1/testicular). The three patients with ovarian cancer were stable for 25 to 42 weeks. In Part A2, the TRAEs (>10%) of any grade were pruritus, rash and rash maculo-papular (each: 20%, n=3), diarrhea (13%, n=2). One confirmed RECIST1.1 partial response (PR) was observed at 800mg in a patient with anti-PD-1 resistant RCC who stayed on study for 30 weeks. Nine patients had best response of SD and five of them were stable for more than 16 weeks (2/head and neck, 1/melanoma, 1/skin squamous cell carcinoma, 1/RCC). SRK-181 treatment resulted in increased levels of circulatory TGFβ1, which suggested target engagement. Part B enrollment is ongoing.
Conclusions
As of 2 June 2022, SRK-181 has been tolerated as monotherapy and in combination with anti-PD-(L)1. No DLT was observed up to 3000mg q3w/2000mg q2w as monotherapy and up to 2400mg q3w as combination treatment. Early evidence of efficacy was observed with prolonged stable disease and a confirmed PR.
