Citations

Abstract Glioblastoma (GBM) is a highly malignant type of adult brain tumor with a poor prognosis. Temozolomide (TMZ), a DNA alkylating agent, has been widely used as an effective first-line chemotherapeutic agent for the treatment of GBM patients. The efficacy of TMZ in GBM depends on the absence of the DNA repair protein MGMT which reverses the DNA damage induced by TMZ. The MGMT promoter is hypermethylated in about 45% of GBMs, resulting in lack of MGMT expression and increased responsiveness to TMZ. TMZ is less effective in MGMT unmethylated GBMs. We propose that EGFR inhibition downregulates MGMT and sensitizes glioma cells to TMZ and a combination of pretreatment with erlotinib followed by TMZ could be a useful therapeutic approach in MGMT expressing GBMs. As our experimental model we used multiple MGMT unmethylated lines from the Mayo Clinic patient derived xenografts (PDXs) panel. Our data demonstrate that exposure of cells to EGFR tyrosine kinase inhibitor erlotinib for 48h results in downregulation of MGMT at the mRNA and protein level. Additionally, EGFR inhibition activates the AP-1 transcription factor and overexpression of AP-1 components Fos and Jun results in decreased MGMT expression in TMZ resistant PDXs, suggesting that AP-1 acts as a transcriptional repressor of MGMT. We further identified that the mice implanted with TMZ resistant PDXs pretreated with afatinib followed by TMZ treatment survived longer compared to those treated with TMZ alone. Thus, the use of EGFR inhibition may enhance the sensitivity of MGMT unmethylated GBMs to TMZ.

Abstract BACKGROUND Glioblastoma (GBM) is an infiltrative, uniformly fatal brain tumor, treated with surgery, radiation, and Temozolomide (TMZ). Chemoradiation induces a senescent-like phenotype, which contributes to disease recurrence. We recently found that, radiated GBM cells can be eliminated by inhibition of BCL-XL. However, it remains unknown whether p53 is involved in this process and whether the elimination of senescent cells by BCL-XL inhibition could be augmented by MDM2 inhibition, a negative p53 regulator. METHODS p53-mutant (GBM6/GBM123) and p53-WT (GBM39/GBM76) human GBM cells were treated with 5Gy or TMZ following 48 hours of MDM2 inhibitor (AMG232) or vehicle treatment and maintained for seven days to establish a senescent-like phenotype. We evaluated the IC50 for BCL-XL inhibitor (A1331852) in radiated vs. non-radiated cells with or without MDM2 inhibitor pre-treatment. RESULTS MDM2-inhibitor treatment prior to radiation increased the expression of p21 and lead to increased cell death when combined with BCL-XL inhibition in p53-WT GBM cells. IC50 of BCL-XL inhibitor after prior MDM2 pretreatment and radiation in GBM76 was 4.5□M compared to 33.5□M, 18.1□M, and 32.3□M in vehicle without radiation, vehicle with radiation, and MDM2 inhibitor-alone treatment groups, respectively(p=0.0036). The IC50 of BCL-XL inhibitor without MDM2-inhibition in non-irradiated and radiated, as well as pre-administration of MDM2 inhibitor in non-irradiated and radiated GBM39 cells was 5618nM, 16117nM, 3926nM and 276.5nM, respectively(p=0.0003). Conversely, MDM2 co-inhibition with BCL-XL did not lead to increased rates of cell death in p53-mutant cell(p>0.05). CONCLUSION We previously identified that BCL-XL inhibition promotes cell death in senescent GBM cells. We build upon that work, demonstrating the increased rates of cell death can be augmented by MDM2 inhibition, but only in p53-WT cells. These findings highlight a novel therapeutic target for treating latent GBM tumors prior to recurrence, with the additional of MDM2 inhibition greatly increasing the efficacy of BCL-XL targeting agents.

Abstract BACKGROUND Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ). Therapy-resistant residual cells persist in a latent state a long time before inevitable recurrence. Conventional radiation and Temozolomide (TMZ) treatment cause oxidative stress and DNA damage resulting senescent-like state of cell-cycle arrest. However, increasing evidence demonstrates escaping senescence leads to tumor recurrence. Thus, the ablation of senescent tumor cells after chemoradiation may be an avenue to limit tumor recurrence. METHODS 100uM TMZ for 7days or 10-20Gy radiation (cesium gamma radiator) was used for senescence induction in human glioblastoma in vitro and confirmed by SA-Beta gal staining and PCR. Replication arrest assessed by automated quantification of cellular confluence (Thermo Scientific Series 8000 WJ Incubator). We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells. RESULTS Among the senolytic tested, the Bcl-XL inhibitors A1331852 and Navitoclax both shown senolytic effect by selectively killing radiated, senescent tumor cells at lower concentrations as compared to 0Gy treated non-senescent cells. Across 12 GBM cell lines, IC50 for senescent cells was 6–500 times lower than non-senescent GBM(p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation has also observed by BCL-XL knockdown in radiated glioma. CONCLUSION These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.

Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF βPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of βPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of βPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover βPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with βPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF βPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.

Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (selinexor), a first in class CRM1 inhibitor recently approved for multiple myeloma and diffuse large B-cell lymphoma (DLBCL), has been limited by substantial adverse effects (AEs). To address this clinical problem, we focused on identifying novel strategies to boost the potency, reduce toxicity, and broaden the applicability of CRM1 inhibitors to a wider range of malignancies. We discovered that salicylates could markedly enhance the anti-tumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. KPT-330 was chosen as the prototypical CRM1 inhibitor given its current FDA approval status and characterized pharmacokinetics; and choline salicylate (CS) was chosen as the prototypical salicylate given its favorable pharmacokinetics and reduced antiplatelet, renal, neurological and gastrointestinal AEs in humans compared to other salicylates. By using cell lines belonging to different hematologic malignancies and solid tumors, we demonstrated ex vivo that the combination of KPT-330 and CS (K+CS) could induce unique and significant antitumor effect at much lower dose of KPT-330 (at 25% of the dose used in the clinic), thereby potentially mitigating prohibitive clinical AEs (Figure 1a-d, and e-g). This significant synergetic antitumor effect observed with K+CS ex vivo was also validated in vivo by using an NSG mouse model of mantle cell lymphoma (Figure 1h). Moreover, the K+CS combination did not show this potent toxic effect on non-malignant cells in vivo and was safe without inducing toxicity to normal organs in NSG mice. Mechanistically, protein profiling through mass spectroscopy revealed that K+CS uniquely affects the cellular pathways of DNA damage repair, DNA synthesis and cell cycle progression. Studies involving immunoblotting, cell cycle analysis, immunofluorescence microscopy assessing nucleocytoplasmic molecular export and DNA damage, reporter assay to assess homologous recombination repair proficiency and immunohistochemistry showed that, compared to KPT-330 treatment alone, K+CS decreased the expression of CRM1, Rad51 and thymidylate synthase proteins in vitro and in vivo, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, and importantly a unique cell cycle arrest in S-phase, thus leading to cell apoptosis. These effects on cellular proteins and pathways were unique to K+CS treatment and were not observed with KPT-330 or CS single agent treatment. Pathway analyses through RNA sequencing also paralleled the findings of proteomic studies thus further validating the unique effect of K+CS treatment on the aforementioned cellular pathways. Importantly, K+CS treatment exerted unique and significant antitumor effect ex vivo on primary malignant cells obtained from patient's with high-risk hematologic malignancies such as double hit DLBCL, BTK and BCL2 inhibitor resistant mantle cell lymphoma, TP53 deleted/mutated chronic lymphocytic leukemia and high-risk multiple myeloma thus signifying its broader applicability as a treatment option for these aggressive hematologic malignancies where there is a dire need to find new treatment strategies (Figure 1i). In summary, we describe a unique all-oral drug combination with a novel constellation of mechanisms of action on cellular pathways that are exploited by cancer cells. K+CS represents a new class of therapy for multiple cancer types and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for therapy of blood cancers. Disclosures Witzig: Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; MorphSys: Consultancy; Immune Design: Research Funding; Spectrum: Consultancy.

Abstract Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Abstract The efficacy of standard radiation therapy (RT) in glioblastoma (GBM) is limited, and there is a strong rationale to develop effective radiosensitizing agents. ATM is a key regulator of DNA damage induced by RT, and small molecule ATM inhibitors have shown radio-sensitizing effects in cancer cells, and may improve radio-sensitivity in GBM. Here, we evaluated the brain penetrant ATM inhibitor AZD1390 in combination with RT in GBM cell lines and patient derived xenografts (PDXs). AZD1390 (30 nM and higher) suppressed ionizing radiation-(5 Gy, IR) induced phosphorylation of ATM-Serine1981 and downstream signaling proteins Kap1, Chk2 and H2AX in GBM established cell lines (U251 and U87) and PDX lines (GBM12, GBM39 and GBM43). In cell cycle analysis, 30nM AZD1390 enhanced the IR induced G2/M arrest in U251 (80.6% with AZD1390/IR vs. 64.6% with IR alone, p= 0.01) and PDX lines GBM43 (61.9% vs. 25.7%, p= 0.01) and GBM39 (40.9% vs. 25.4%, p= 0.01). Moreover, in a U251 clonogenic survival assay, AZD1390 sensitized cells to IR-(5 Gy) induced killing (0.24% survival with AZD1390/RT vs. 2.3% with IR alone, P=0.01). For in vivo radiation combination studies, mice with established orthotopic tumors were irradiated to the cerebrum through opposed laterals with a 225 kVp stereotactic animal irradiator. While the hard palate and upper tongue were in the radiation target, the oropharynx and hypopharynx were spared with this radiation set up. A pilot study of RT combined with AZD1390 was evaluated in mice with established U251 orthotopic tumors using cohorts of 5 mice per arm. AZD1390 was given concurrently with conventionally fractionated radiation (2 Gy x 5 fractions) at a dose of 20 mg/kg PO delivered either daily or twice daily, with or without the efflux inhibitor elacridar. RT alone was well tolerated with minimal weight loss but was ineffective (median survival 30 days vs. 33 days in control group, p=0.5). In contrast, all of the RT/AZD1390 treatment arms exhibited enhanced but tolerable weight loss and had significant extension in symptom-free survival that currently extends beyond 65 days (median survival no reached). In conclusion, AZD1390 is an effective radio-sensitizer in vitro, and survival benefit from AZD1390 combined with conventionally fractionated RT in U251 models is encouraging. Further evaluation of efficacy across additional PDX models and careful analysis of the pharmacodynamic effects in tumor vs. normal tissues will be important to understand the therapeutic window for this agent in combination with RT. Citation Format: Jiajia Chen, Shiv K. Gupta, Gaspar J. Kitange, Ann C. Mladek, Brett L. Carlson, Lihong He, Zeng Hu, Katrina K. Bakken, Danielle M. Burgenske, Margaret A. Connors, Jann N. Sarkaria. Targeting ATM with AZD1390 for radio-sensitization of glioblastoma patient derived xenografts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6506.

Abstract Despite aggressive treatment that involves surgery, radiation and temozolomide therapy, a significant morbidity from glioblastoma (GBM) recurrence highlights the pressing unmet medical need to develop effective novel therapies for GBM. Murine Double Minute 2 (MDM2) is an important regulator of the p53 tumor suppressor, which promotes cell cycle arrest and apoptosis in response to DNA damage. Here we have assessed the efficacy of RG7388, a purported brain penetrant MDM2-inhibitor, alone or combined with radiation therapy (RT) in patient-derived xenograft (PDX) models of GBM. In vitro, RG7388 suppressed viability of GBM PDX short-term stem cell cultures of p53 wildtype lines with MDM2-amplification (GBM46 and 108, IC50 25 and 11 nM, respectively) or without MDM2-amplification (GBM10 and 14, IC50 43.5 and 9.1 nM, respectively). Serum proteins appear to reduce efficacy of RG7388, which is supported by the notion that adding 2.5% bovine serum albumin to a serum free stem cell cultures increased the IC50 by 3 to 5 fold. At the molecular level, both RG7388 and RT could induce p53 signaling in GBM10, but a more robust induction was observed with the combination. In athymic nude mice, RG7388 readily distributes into normal brain as measured by LCMS-MS at 1 hour after five daily oral doses (70 mg/kg) the average RG7388 concentrations in brain and plasma were 2167 ng/g and 4423 ng/ml, respectively. In an initial efficacy study using flank tumors established from GBM10, one week of dosing at 70 mg/kg/day RG7388 alone was ineffective, while combining RG7388 with focal radiation (4 daily doses of 5 Gy each) had a moderate 15 day delay in tumor progression. However, in an MDM2-amplified GBM108 line with a relatively intact blood-brain barrier, one week of daily RG7388 dosing, either alone or in combination with RT was remarkably effective (median survival 71 days with RG7388 alone vs. 29 days with vehicle, p<0.0001; and 262 days for RG7388/RT vs. 74 days with RT, p=0.017). Taken together, RG7388 alone or in combination with RT is highly effective in an MDM2-amplified pre-clinical model of GBM. Determining impact of serum protein binding on drug pharmacokinetics and further evaluation of pharmacodynamic effects and orthotopic therapy in additional p53 wildtype PDX lines will help to increase our understanding if RG7388/RT therapy can be used in a larger population of GBM tumors. Citation Format: Shiv K. Gupta, Ann C. Mladek, Surabhi Telele, Afroz S. Mohammad, Lihong He, Zeng Hu, Katrina K. Bakken, Danielle M. Burgenske, Brett L. Carlson, William F. Elmquist, Jann N. Sarkaria. Brain penetrant MDM2 inhibitor RG7388 extends survival benefit of radiation treatment in select glioblastoma patient-derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6276.

Abstract New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, as it does in AR-positive prostate and breast cancers. Using RNAseq, immunoblot and immunohistochemistry, we found that nearly half of GBM cell lines, patient-derived xenografts and human tumors express AR transcript and protein with levels that overlap those of primary prostate cancer. AR expression in GBM did not vary by sex, age or common molecular alterations. We identified two cell line models of GBM that expressed AR protein (LN18 and T98G: termed “AR positive”) and two that did not (8MGBA and AM38: termed “AR negative”). Seviteronel, a blood-brain barrier permeable CYP17 lyase inhibitor and antiandrogen slowed growth in AR positive GBM cell lines (GI50 3-4 µM) but not AR negative lines (GI50 > 500 µM) as measured by the colony formation assay. The antiandrogen enzalutamide, which also penetrates the blood brain barrier, similarly preferentially slowed growth in AR positive GBM cell lines. Seviteronel and enzalutamide sensitized AR positive GBM cell lines to radiation with enhancement ratios of 1.3-1.6 as measured by the clonogenic survival assay. Antiandrogens had no effect on the radiosensitivity of AR negative GBM cell lines. Seviteronel treatment did not affect the growth of AR positive T98G xenografts grown in vivo, but did sensitize these tumors to radiation (median time to tripling: 15 d with radiation alone and not reached with radiation combined with seviteronel). Enzalutamide similarly had modest single agent effects on an AR positive GBM patient-derived xenograft (GBM26 from the Mayo Clinic GBM PDX national resource) grown in vivo but sensitized these tumors to radiation (median time to tripling: 25.5 d with radiation alone and 39 d with radiation combined with enzalutamide). RNAseq performed on GBM26 tumors grown in vivo revealed that enzalutamide treatment caused minimal transcriptional changes when given as monotherapy but, when given in combination with radiation, blocked the ability of AR-positive GBMs to engage adaptive transcriptional programs related to multiple DNA repair pathways. We confirmed these mechanistic findings in vitro, as antiandrogens selectively impaired the repair of radiation-induced double strand DNA breaks in AR positive GBM cell lines. These results suggest that AR signaling may mediate therapy resistance in AR positive GBMs, and patients with these tumors could derive clinical benefit from combination therapies involving radiation and blood-brain-barrier permeable antiandrogens. Citation Format: Christian K. Werner, Uchechi Nna, Hanshi Sun, Kari Wilder-Romans, Joseph Dresser, Ayesha Kothari, Weihua Zhou, Yangyang Yao, Arvind Rao, Stefanie Stallard, Carl Koschmann, Tarik Bor, Waldemar Debinski, Alexander Hegedus, Meredith Morgan, Sriram Venneti, Edwina Baskin-Bey, Daniel Spratt, Howard Colman, Jann Sarkaria, Arul Chinnayain, Joel Eisner, Corey Speers, Theodore S. Lawrence, Roy Strowd, Daniel R. Wahl. Repurposing antiandrogens to overcome therapy resistance in androgen receptor-positive glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6267.

Abstract Robust function of the p53 tumor suppressor pathway is critical when treating with DNA-damage inducing agents such as radiation therapy (RT), which is a key component of standard care for GBM. MDM2 is an important negative regulator of p53 stability and MDM2 is amplified in approximately 14% of GBM. Based on the concept that suppression of MDM2 can reactivate p53 function and potentially have single agent or combinatorial effects, multiple MDM2 inhibitors have been developed. Here we report in vitro and in vivo efficacy and pharmacodynamic (PD) effects of a BBB-penetrant MDM2-p53 antagonist, BI-MDM2, in GBM patient-derived xenograft (PDX) models. In vitro studies in p53 wild-type (WT) lines with or without MDM2 amplification demonstrate IC50 values in cell viability assays of 2-12 nM in serum-free culture and 5-35 nM in serum-containing culture after seven days of treatment. In vivo studies were performed in p53 WT lines: the MDM2-amplified GBM108, and the non-amplified GBM14, grown as orthotopic tumors in nude mice. Weekly oral treatment at 2 mg/kg of BI-MDM2 doubled median survival (placebo, 28 days (d) vs 2 mg/kg BI-MDM2, 57 d. p<0.0001) while weekly dosing at 10 mg/kg extended the median over 5 fold (176 d. p<0.0001) with half of the mice still living at 223 days post-inoculation. To assess the PD properties of this compound, mice bearing orthotopic GBM108 were treated three weeks after inoculation with a single dose of 2 or 10 mg/kg BI-MDM2. Normal brain, tumor, and plasma were collected at 24 and 48 hours (h) after dosing and downstream p53 transcriptional targets, p21 and PUMA were evaluated by qRT-PCR. p21 mRNA relative quantification detection at 24h increased by 1.5-10.5-fold in the 2 mg/kg group of animals compared to vehicle while the 10 mg/kg dose led to an increase by 2-25 fold compared to vehicle. PUMA was minimally affected by the 2 mg/kg dose but increased 1.2-17-fold over vehicle in the 10 mg/kg group at 24h. The observed increases in p21 and PUMA varied little between the 24 and 48h timepoints. In an orthotopic GBM14 PDX efficacy study, BI-MDM2 was combined with 20 Gy RT delivered in 10 fractions over 2 weeks with dosing limited to 2 weeks of therapy or until mice reached a moribund state. While two doses of 10 mg/kg BI-MDM2 alone had a modest effect on survival (41 d vs 31 d with placebo; p=0.002), continued dosing until moribund further extended median survival (82 d with BI-MDM2; p=0.001). The combination of two doses of BI-MDM2 with 2 weeks of RT extended survival as compared to RT alone (107 d vs. 69 d, respectively; p=0.019), while with extended drug dosing combined with 2 weeks of RT, median survival has not yet been reached (>125 d). Taken together, these results suggest that BI-MDM2 is a promising therapeutic agent that may provide significant anti-tumor efficacy either alone or in combination with RT in both MDM2 amplified and non-amplified p53 WT patients. Citation Format: Ann C. Mladek Tuma, Shiv Gupta, Surabhi Talele, Afroz Shareef Mohammad, Katrina K. Bakken, Helen He, Zeng Hu, Margaret A. Connors, Danielle M. Burgenske, Brett L. Carlson, William F. Elmquist, Ulrike Weyer-Czernilofsky, Jann N. Sarkaria. A promising blood-brain-barrier penetrant MDM2-p53 antagonist, BI-MDM2, increases survival in orthotopic, glioblastoma patient-derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4190.