Kase, Adam M.

The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over 90% of kidney tumors are renal cell carcinomas, of which, clear cell is the most predominate histologic subtype. Von Hippel Lindau (VHL) gene alterations result in the overexpression of growth factors that are central to the pathogenesis of clear cell carcinoma. The therapeutic strategies have revolved around this tumor suppressor gene and have led to the approval of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor (VEGF) axis. The treatment paradigm shifted with the introduction of immune checkpoint inhibitors (ICI) and programed death-1 (PD-1) inhibition, leading to durable response rates and improved survival. Combinations of TKI and/or ICIs have become the standard of care for advanced clear cell renal cell carcinoma (ccRCC), changing the outlook for patients, with several new and promising therapeutic targets under development.

The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2 (Xofigo®), are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well-known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA)-, gastrin-releasing peptide receptor (GRPR)-, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.

AbstractPatients with relapsed follicular lymphoma who do not respond to CAR‐T have a poor outcome. We present a case of refractory follicular lymphoma who relapsed after two CAR‐T infusions and achieved a complete remission after treatment with obinutuzumab and lenalidomide. This represents a promising treatment option in the post‐CAR‐T setting.

Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET–CT and negative conventional imaging to positive PSMA PET–CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET–CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.

176 Background: Despite androgen deprivation therapy, prostate cancer will develop resistance known as castrate resistant prostate cancer (CRPC). Androgen signaling is associated with pathways that influence cell proliferation and survival via cell cycle regulation. AR signaling results in inactivation of Rb tumor suppressor by way of AKT and reduction in intrinsic CDK4/6 inhibitors. Since PTEN loss is found in 40% of mCRPC and AKT pathway is a mechanism of CDK4/6 inhibitor resistance, we hypothesize adding an AKT inhibitor to a CDK4/6 inhibitor will have synergistic activity while delaying CDK4/6 inhibitor resistance. Preclinical xenografts have been shown to recapitulate patient response, therefore, can be used to guide clinical trials using novel combinations. Methods: We have established patient derived tumor xenograft models (GUR-017M, TMA-027 and PRJ-88T) from patients with mCRPC with each having a unique genomic alteration profile. In the clinical setting, GUR-017M was resistant to abiraterone, enzalutamide, cabazitaxel and had exposure to docetaxel. TMA-027 and PRJ-88T were resistant to enzalutamide. We combined a CDK4/6 inhibitor with an AKT inhibitor and treated each of these patient tumors in NOD-SCID mice for a total duration of 40 days. Mice were implanted and separated into 4 groups (placebo, CDK4/6 inhibitor, AKT inhibitor and CDK4/6 + AKT inhibitor) with 10-13 mice in each group. Tumor volumes were measured twice a week. For GUR-017M, abemaciclib (50 mg/kg) was combined with MK2206 (120 mg/kg) and was compared to each placebo and each single agent alone. For TMA-027, palbociclib (50 mg/kg) was combined with ipatasertib (50 mg/kg). After 40 days, tumors were harvested for immunohistochemistry analysis. PRJ-88T was grown as 3D spheroids in ultra-low attachment plates and treated with palbociclib + ipatasertib (10 uM-100uM) to evaluate for synergy. Results: GUR-017M and TMA-027 showed significant delayed tumor growth compared to placebo or either single agent alone. In the GUR-017M group, the final mean tumor volume for the combination group was 149 mm3, compared to 377 mm3 (abemaciclib), 358 mm3 (MK2206) and 527 mm3 placebo group, representing a percent decrease compared to control by 72%, 29%, and 32%, respectively. For TMA-027, the final mean tumor volume for the combination group was 102 mm3, compared to 259 mm3 (palbociclib), 416 mm3 (ipatasertib), and 402 mm3 placebo group, representing a percent decrease compared to control by 75%, 36%, and 4%, respectively. PRJ-88T 3D spheroids showed synergy with palbociclib + ipatasertib. In vivo experiments using PRJ-88T are in progress. Conclusions: The preclinical results show combining CDK4/6 inhibitors with AKT inhibitors is a promising treatment strategy and provides the basis for a clinical trial in patients with mCRPC.

Patients with relapsed follicular lymphoma who do not respond to CAR-T have a poor outcome. We present a case of refractory follicular lymphoma who relapsed after two CAR-T infusions and achieved a complete remission after treatment with obinutuzumab and lenalidomide. This represents a promising treatment option in the post-CAR-T setting.

Abstract Targeted therapy in prostate cancer is in its early stages and has a promising future since many genomic alterations in metastatic castrate resistant prostate cancer (mCRPC) do not have FDA approved agents for this indication. Three-dimensional culture has been shown to recapitulate patient response to therapy. We characterized a unique patient tumor-derived, GUR017M, 3D culture spheroid model and tested novel therapies based on its genomic profile. This tumor was obtained from a patient with mCRPC who progressed on enzalutamide, abiraterone, cabazitaxel, and had exposure to docetaxel, however discontinued due to toxicity. In order to characterize and test novel therapies for mCRPC, a 3-D spheroid drug assay was utilized and was able to recapitulate the GUR017M response to previous therapies (resistance to docetaxel and enzalutamide). Using a 3-D spheroid drug assay, single agents were investigated based on the GUR017M genomic profile which included cyclin D1, LYN, and FGF3/4/19 amplifications along with HRAS Q61R mutation, and TP53 splice site 672+2T>G. Single agents (abemaciclib, bafetinib, erdafitinib, tipifarnib, MK2206, APR-246) all caused dose dependent inhibition up to 100% inhibition. This rare prostate cancer model, GUR017M allows us to test novel single agents and combination strategies in 3-D culture. This patient tumor has also proven to be a successful PDTX model which allows for confirmatory testing in animal models in order to move forward with clinical trial proposals. Citation Format: Adam M. Kase, Winston Tan, John A. Copland. Characterization and targeted therapy using patient tumor-derived 3-D spheroids in a metastatic castrate resistant prostate cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2640.

Abstract The increase in fatty acid metabolism is a hallmark of cancer. Stearoyl CoA desaturase (SCD) is an endoplasmic reticulum (ER) enzyme that catalyzes D9 cis désaturation of fatty acyl-CoA substrates. One of its isoforms, SCD1, is overexpressed in several cancers including breast cancer. The higher expression of SCD1 in breast cancer patients correlates with significantly shorter relapse-free and overall survival rates, indicating that SCD1 may be a therapeutic target. We have previously developed and published a novel SCD1 inhibitor, SSI4. Metabolic reprogramming facilitates tumor growth by promoting immune suppression in tumors. Fundamental metabolic processes like fatty acid (FA) metabolism are involved in T cell activation and differentiation and their modulation can differentially affect the development of T helper cell lineages. FA synthesis and oxidation are essential for the development and functioning of CD8+ T memory cells and are contributing factors that influence CD4+ T effector and Treg cell development. These associations between metabolism and immune cells lead us to our hypothesis that aberrant de novo lipogenesis is linked to immune suppression. Thus, SCD1 inhibitors should increase anti-tumor immunity. We evaluated the effect of SSI4-mediated SCD1 inhibition in two mouse triple negative breast cancer cell lines. The data showed that SSI4 stimulates calreticulin (CRT) translocation to cell membrane. CRT is an ER resident protein that translocates to the cell surface under ER stress conditions. Cell surface expression of CRT is known to induce immune responses including phagocytosis, translocation of cancer antigen to the cell surface, and apoptosis. We are currently studying the effect of CRT translocation in our model. A major focus of our project is to assess the efficacy of combination treatment of SSI4 and an immune checkpoint blockade. To this end, this combination therapy synergistically blocked E0771 tumor growth in vivo. Further, to understand the immune responses generated, we performed immunohistochemical analysis of the tumors (day 20 post-treatment) indicating that the combination therapy resulted in higher membrane localized CRT, supporting our rationale that CRT translocation is involved in mediating the anti-tumor responses. Flow cytometry analysis indicated that the combination treatment increased immune cell infiltration. Specifically, SSI4 treatment induced infiltration of double negative T cells, natural killer cells and macrophages, suggesting that it promoted a pro-inflammatory immune response. SSI4 treatment down regulated immune suppressive cells including Tregs, dendritic cells and mesenchymal derived stem cells. The response of cancers with low and intermediate tumor mutational burden such as breast cancer to immune checkpoint inhibition is limited. Our data indicates that combination treatment of SSI4 and anti PD1 is a promising therapeutic strategy. Citation Format: Sneha Vivekanandhan, Justyna Trynda, Laura A. Marlow, Barath shreeder, James L. Miller, Adam M. Kase, Winston Tan, Keith L. Knutson, John A. Copland. SCD-1 blockade sensitizes triple negative breast cancer to immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1484.

230 Background: Inpatient mortality review is commonly used to improve patient care. Individual review of outpatient deaths is less common, yet 30-day mortality after hospital stay is an important quality metric. In this study, we sought to identify opportunities for care improvement by reviewing outpatient mortalities for cancer patients who died within 30 days of hospitalization. Methods: We identified 48 patients at Mayo Clinic Florida, with a hematologic (heme) or solid tumor (onc) cancer, who died within 30 days of an index hospital stay in 2018. We created a 32-question review survey to address quality of care around the hospital stay. The review team consisted of 1) heme or onc attendings, 2) heme/onc fellows, and 3) palliative care attendings. Each case was reviewed by one member of each of the 3 groups, split into heme or onc cases. Discrepancies in objective data points were resolved by the research team. Results: Of 143 surveys sent to 13 physicians (3 heme), 112 responses from 11 physicians (1 heme) for 47 patients were received. Twenty-one patients (45%) received cancer therapy within 30 days of death, and 23 (49%) were admitted >2 times in 2 months prior to death. For onc cases, attendings rated prognosis as discussed 83% of the time, vs 65% of fellows and 39% of palliative care; in heme cases, the attending rated prognosis as discussed 11% of the time, vs 86% of fellows and 50% of palliative care. In heme cases, the attending rated expected survival <3 months in 33% of cases vs 71% by fellows and 89% by palliative care; in onc cases, the reviews were more consistent (79% attending, 85% fellow, 93% palliative care). See Table for timing of prognosis discussions and palliative care involvement. Conclusions: The most common improvement opportunities identified by reviewing heme/onc patients who died within 30 days of a hospital stay included documented prognosis discussion and involvement of palliative care. Opportunities differed between heme and onc patients. Future directions include identifying and mitigating barriers that providers face in reaching these goals for their patients. [Table: see text]

356 Background: Approval of multiple therapeutic agents for castrate resistant prostate cancer (CPRPC) has improved survival and also quality of life. However, how to optimize sequencing is still an ongoing challenge for most clinicians. Methods: A retrospective chart review of patients treated with FDA approved regimens for castrate resistant prostate cancer from 2002 to 2017 at Mayo Clinical Florida was completed. Data on progression free survival of the various treatment sequences including abiraterone, docetaxel, and enzalutamide were reviewed. Results: One hundred patients were included in the study. Those on clinical trial were excluded. All patients were on LHRH agonist /antagonist and were continued while on the subsequent treatments. The first line therapy progression free survival (PFS) was 245 days with abiraterone acetate (AA), 307 days with enzalutamide (E) and docetaxel 285 days, respectively. The second line therapy PFS was 201 days with AA and 166 days with E. When AA was given after E PFS was 97 days and when E was given after AA the PFS was 68 days. E given after docetaxel resulted in a PFS of 390 days for one patient. Conclusions: In this chart review, enzalutamide had the longest PFS when used as the first line therapy and the PFS was improved when used as a second line after docetaxel. This retrospective review suggests therapy sequencing may be optimized to increase progressive free survival in patients with metastatic castrate resistant prostate cancer.