Additional Treatment Options Research Articles

Abstract 6215: Peposertib, a DNA-PK inhibitor, enhances the antitumor efficacy of anthracyclines in triple-negative breast cancer models in vitro and in vivo

Abstract Background: Triple-negative breast cancer (TNBC) is the most lethal breast cancer subtype, exhibiting poor response rates toward current chemotherapy regimens and lacking additional effective treatment options. Approximately 30% of patients with TNBC respond well to anthracycline/taxane-based standard-of-care chemotherapy regimens. However, remaining patients demonstrate limited improvements in clinical outcomes, highlighting the critical need for effective strategies to improve anthracycline/taxane-based chemotherapy (1, 2). DNA-dependent protein kinase (DNA-PK), a member of the phosphoinositide 3-kinase-related kinase protein family, promotes nonhomologous end joining (NHEJ) as part of the DNA damage response. Peposertib is a potent, selective, and orally bioavailable DNA-PK inhibitor that strongly potentiates the antitumor effects of ionizing radiation and DNA double-strand break-inducing agents, including anthracyclines, in preclinical models. Here we report the synergistic antitumor effects of peposertib combined with topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC models in vitro and in vivo. Methodology: Combinations of peposertib with TOPO II inhibitors were evaluated in TNBC cell lines by viability assays, immunoblotting, and flow cytometry. Gene expression analysis was performed using the nCounter PanCancer pathways panel and results were confirmed by quantitative polymerase chain reaction (qPCR). In vivo efficacy was assessed in cell-line derived and patient-derived xenograft models. Results: When administered in combination with doxorubicin, epirubicin, and etoposide, peposertib exhibited synergistic antiproliferative activity in TNBC cell lines in vitro. The downstream analysis of pharmacodynamic biomarkers revealed induction of NHEJ mediated repair upon TOPO II inhibitor treatment and provided mechanistic insights into the synergistic antitumor effects of peposertib combined with TOPO II inhibitors. Furthermore, this combination treatment induced ataxia telangiectasia mutated (ATM)-dependent compensatory signaling and inflammatory responses, potentially creating a proinflammatory tumor microenvironment. To evaluate whether peposertib enhanced the antitumor effects of TOPO II inhibitors in vivo, we established a well-tolerated preclinical treatment schedule for the combined use of peposertib and pegylated liposomal doxorubicin, which was capable of achieving tumor regression in patient- and cell line-derived xenograft models of TNBC. Conclusion: Our findings suggest that cotreatment with the DNA-PK inhibitor peposertib can enhance the efficacy of anthracycline/TOPO II-based chemotherapies. This work was supported by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). 1) Davison C et al. NPJ Breast Cancer. 2021;7(1):38. 2) Bianchini G et al. Nat Rev Clin Oncol. 2016;13(11):674-690. Citation Format: Steffie Revia, Christian Sirrenberg, Antonia Schach, Astrid Zimmermann, Frank T. Zenke, Joachim Albers. Peposertib, a DNA-PK inhibitor, enhances the antitumor efficacy of anthracyclines in triple-negative breast cancer models in vitro and in vivo. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6215.

Abstract 6156: MALT1 protease inhibition overcomes BTK inhibitor resistance and shows synergistic activity with venetoclax in models of B cell lymphoma and leukemia

Abstract Introduction: Specific B cell malignancies, including CLL and the aggressive non-GCB subtype of DLBCL, are driven by constitutive activation of the B cell receptor (BCR) pathway and the transcription factor NF-κB. Pharmacological inhibition of MALT1 protease, a key mediator of the BCR/NF-κB signal transduction pathway, may therefore provide an attractive treatment option for patients with these cancers. Further, as combination therapy is often required for the treatment of aggressive B cell malignancies, the identification of therapies that synergistically combine with MALT1 inhibitors could afford additional and promising treatment options. Experimental Procedures: A highly potent and orally bioavailable MALT1 protease inhibitor (ABBV-MALT1) was used to test the hypothesis that MALT1 inhibition will abrogate the proliferation of preclinical models of B cell malignancies in vitro and in vivo. Tumors treated with ABBV-MALT1 were subjected to transcriptomic and functional proteomic assays to elucidate molecular mechanisms of action and rational combination partners. Results: Mechanistic studies reveal that ABBV-MALT1 effectively inhibits signal transduction of the BCR pathway and reduces NF-κB gene activation in non-GCB DLBCL cell lines resulting in cell cycle arrest and diminished viability. In vivo, oral administration of this compound demonstrates robust tumor growth inhibition in several models of B cell tumors, including non-GCB DLBCL models that are resistant to Bruton’s tyrosine kinase (BTK) inhibitors. NF-κB target genes include the pro-survival family members BCL-XL and BCL2-A1, which aid in regulation of the intrinsic apoptosis pathway. As ABBV-MALT1-induced inhibition of the NF-κB pathway resulted in downregulation of these genes, we hypothesized that the associated tumor models would become increasingly dependent on the pro-survival family member BCL-2. To test this hypothesis, combination studies of ABBV-MALT1 and the selective BCL-2 inhibitor venetoclax were performed in both cell line and patient-derived xenograft models of DLBCL. Herein we show that concomitant administration of ABBV-MALT1 and venetoclax results in dramatic antitumor activity in all models tested in vivo. This efficacy also translates to primary patient CLL cells in vitro where the combination confers greater levels of apoptosis compared to either agent alone. Conclusion: ABBV-MALT1 demonstrates robust single agent anti-tumor activity in malignant B cell models that are resistant to BTK inhibitors. Moreover, combination of ABBV-MALT1 with the BCL-2 inhibitor venetoclax shows synergistic cell killing of B cell tumors in vitro and dramatic tumor regression in vivo. Together, these data indicate that MALT1 inhibition may overcome BTK inhibitor resistance and combine with venetoclax to effectively treat patients with B cell malignancies. Citation Format: Joshua P. Plotnik, Raghuveer S. Mali, Velitchka Bontcheva, Colleen Dowell, Jun Chen, Adam E. Richardson, Ryan A. McClure, Paul Jung, Lan Pham, Andrew J. Souers, Jonathan A. Meulbroek, William N. Pappano. MALT1 protease inhibition overcomes BTK inhibitor resistance and shows synergistic activity with venetoclax in models of B cell lymphoma and leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6156.

Abstract 167: Assessment of homologous recombination deficiency cancer signatures with patient-derived tumor organoid models

Abstract BRCA1/2 alterations are commonly used markers to characterize homologous recombination deficiency (HRD) in cancer. Deficiency in the DNA double-strand break repair mechanism can cause tumor vulnerability to platinum and poly (ADP-ribose) polymerase inhibitor (PARPi) through synergistic lethal mechanisms. However, PARPi resistance is observed among some BRCA-mutant cancer patients. Conversely, some wild-type BRCA1/2 cancers are susceptible to these therapies. Hence, there is a need to better characterize HRD cancers and uncover additional treatment options. Patient-derived tumor organoids (PDTOs) are emerging ex vivo cancer models as they harbor the mutational landscape of the original tumor and are shown to accurately replicate drug responses observed in patients. In this project, we used a diverse set of pan-cancer PDTOs to model HRD responses to PARPi and other therapies. A total of n=230 pan-cancer PDTOs were generated and characterized by cytopathology, immunohistochemistry, and NGS platforms, confirming concordance with corresponding tumors. Fifty PDTOs from patients with and without BRCA1/2 mutations and from patients who received platinum or PARPi were selected for this project, including ovary, breast, pancreas, endometrium and gastrointestinal cancers. HRD of the original cancers was determined by their genomic composition and manual curation of single base substitution molecular signatures and structural variants - a novel classifier trained and validated in our pan-cancer whole-genome sequencing (WGS) cohort. Mutational status of genes in HR pathway was recorded only for PDTOs that have whole exome sequencing (WES). We developed an immunofluorescent staining to detect RAD51 foci and support the functional HR status and evaluated the treatment timeline with daily brightfield imaging to record the effect of PARPi. We performed high throughput drug screening (HTDS) on 11 PDTOs with FDA-approved drugs, including DNA synthesis inhibitors, CHEK1 inhibitors, PARPi, and ATM/ATR inhibitors. Four PDTOs (rectum, ovary, and prostate) with BRCA1/2 alterations and 3 wild-type BRCA1/2 (pancreas and ovary) responded to PARPis; while 4 wild-type BRCA1/2 (pancreas and ovary) did not respond. Only 5 PDTOs were sensitive to platinum therapies, but all 11 PDTOs responded to the CHEK1 and ATM/ATR inhibitors. Further HTDS experiments on the rest of the selected PDTOs, including combination therapies, are ongoing. In this project, our combinational approach includes well-characterized pan-cancer PDTOs, a functional assay to determine the effects of genetic variants, and an innovative HTDS pipeline to assess HRD status. These robust and clinically relevant assays will help uncover alternative therapeutic options for patients with HRD cancers. Citation Format: Hui-Hsuan Kuo, Madj Al Assaad, John Nguyen, Jenna Moyer, Hamza Gokozan, Sarah Ackermann, Jared Capuano, Jyothi Manohar, Michael Sigouros, Andrea Sboner, Juan Miguel Mosquera, Olivier Elemento, Maria Laura Martin. Assessment of homologous recombination deficiency cancer signatures with patient-derived tumor organoid models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 167.

Abstract 1200: Aurora kinase A is a potential therapeutic target regulated by the MYCN oncogene in human retinoblastoma

Abstract Retinoblastoma (RB) is a pediatric intraocular neoplasm characterized by loss of function mutations in the RB1 gene. RB has a near-perfect prognosis in developed countries, but a significant dip in patient survival is observed in low and middle-income nations, with an overall survival rate of around 40%. Chemotherapy is a primary treatment modality in RB. However, the immediate and long-term side effects of conventional and intra-arterial chemotherapies necessitate the need for additional treatment options. Aurora kinases are serine/threonine kinases that play a pivotal role in mitosis. In recent years, Aurora kinase A (AURKA) has gained prominence as a drug target in various tumors and several small molecule inhibitors of AURKA are currently in clinical development. In this study, we have shown that AURKA is overexpressed in RB patient specimens and cell lines using immunohistochemistry and immunoblotting. Moreover, induced expression of AURKA significantly correlated with optic nerve invasion of the tumor suggesting a role of AURKA in RB progression. Inhibition of AURKA in RB cell lines and patient specimens using small molecule inhibitors or selective silencing with lentivirus-mediated shRNA knockdown led to decreased cell viability, increased apoptosis, cell cycle arrest at G2/M phase and subsequent induction of polyploidy. To further investigate the deleterious effects of AURKA inhibition within the tumor microenvironment, chorio-allantoic membrane (CAM) xenografts with RB cells were performed. The in-ovo data revealed a delay in tumor growth when treated with AURKA inhibitors. MYCN is an essential oncogene in RB progression immediately to RB1 mutations. Notably, an in-silico promoter analysis predicted the presence of MYCN binding sites upstream of the transcription start site of AURKA. Chromatin immunoprecipitation - qPCR (ChIP-qPCR) confirmed the binding of MYCN to the promoter region of AURKA. Besides, immunoblots corroborated that AURKA was downregulated in MYCN knockdown RB cells. Overall, our findings show that elevated AURKA levels in RB could be targeted in-vitro and in-ovo, and its expression is transcriptionally regulated by the MYCN oncogene. These data not only shed light on the role of AURKA in RB tumorigenesis but also unravel its potential as a therapeutic target, in isolation or through MYCN-driven downstream pathways. Acknowledgements: Department of Biotechnology - Innovative Young Biotechnologist Award (DBT-IYBA to MMR), Ministry of Science and Technology, Government of India; Hyderabad Eye Research Foundation (HERF), L V Prasad Eye Institute, Bhubaneswar, India; Indian Council of Medical Research - Senior Research Fellowship (ICMR-SRF to NAB), Ministry of Health and Family Welfare, Government of India. Citation Format: Naheed Arfin Borah, Ruchi Mittal, Devjyoti Tripathy, Swathi Kaliki, Suryasnata Rath, Srinivas Patnaik, Mamatha M. Reddy. Aurora kinase A is a potential therapeutic target regulated by the MYCN oncogene in human retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1200.

Benefit and risk evaluation of quinapril hydrochloride

ABSTRACT Introduction Angiotensin-converting enzyme (ACE) inhibitors are a mainstay of antihypertensive therapy. Quinapril hydrochloride, a less commonly used, and less-studied ACE inhibitor has been approved for its primary use in hypertension. Studies also indicate its off-label use for congestive heart failure and diabetic nephropathy. The ANDI and TREND trials have been pivotal in demonstrating the effectiveness of quinapril. Areas covered The authors conducted a review of the literature analyzing the clinical efficacy and safety profile of quinapril. This review discusses the development of quinapril, provides an updated summary of the indications and contraindications, and presents a comparison with other ACE inhibitors. Expert opinion Quinapril is a safe and well-tolerated antihypertensive medication with a favorable safety profile compared to other ACE inhibitors. However, a lack of ample recent clinical trials and post-marketing data investigating the efficacy of quinapril in large cohorts has resulted in limited use in clinical practice. Quinapril may be an effective antihypertensive option for elderly populations as well as those who cannot tolerate the side effects profiles of other ACE inhibitors and as an additional treatment option for patients with heart failure with preserved ejection fraction.

Direct Oral Anticoagulants: How Do These Drugs Work, How to Monitor, and What Is Their Role in Orthopaedic Surgery.

Postoperative venous thromboembolism is a major adverse event associated with orthopaedic surgery. With the addition of perioperative anticoagulation and antiplatelet therapy, the rates of symptomatic venous thromboembolism have dropped to 1% to 3%, and as such, practicing orthopaedic surgeons must be familiar with these medications, including aspirin, heparin, or warfarin, and the use of direct oral anticoagulants (DOACs). DOACs are increasingly being prescribed due to their predictable pharmacokinetics and increased convenience, as they do not require routine monitoring, and 1% to 2% of the general population is currently anticoagulated. Although the introduction of DOACs has yielded additional treatment options, this has also led to confusion and uncertainty regarding treatment, specialized testing, and when and what reversal agents are appropriate. This article provides a basic overview of DOAC medications, their suggested use in the perioperative setting, effects on laboratory testing, and consideration for when and how to use reversal agents in orthopaedic patients.

Prevalence of lymphedema among Anderson-Fabry disease patients: A report from the Fabry registry.

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease due to a genetic variation in the α-galactosidase A (GLA) gene. As a result, the activity of the α-galactosidase A (AGAL-A) enzyme is reduced or absent, which causes sphingolipid deposition within different body parts. AFD typically manifests with cardiovascular, renal, cerebrovascular, and dermatologic involvement. Lymphedema is caused by sphingolipid deposition within lymphatics. Lymphedema can cause intolerable pain and limit daily activities. Very limited data exist on lymphedema in AFD patients. Using data from the Fabry Registry (NCT00196742) with 7671 patients included (44% males and 56% females), we analyzed the prevalence of lymphedema among AFD patients who were ever assessed for lymphedema and studied the age of first reported lymphedema. Additionally, we assessed whether patients received AFD-specific treatment at some point during their clinical course. The data was stratified by gender and phenotype. Our study showed that lymphedema occurred in 16.5% of the Fabry Registry patients who were ever assessed for lymphedema (n = 5487). Male patients when compared to female patient have higher prevalence (21.7% vs 12.7%) and experienced lymphedema at a younger age (median age at first reported lymphedema of 43.7 vs 51.7 years). When compared to other phenotypes, classic phenotype has the highest prevalence of lymphedema with the earliest reported lymphedema. Among those who reported lymphedema, 84.5% received AFD-specific treatment during their clinical course. Lymphedema is a common manifestation of AFD in both genders, with a tendency to present later in female patients. Recognition of lymphedema can offer an important opportunity for intervention and potential impact on associated morbidity. Additional future studies are needed to characterize the clinical implications of lymphedema in AFD patients and identify additional treatment options for this growing population.

Nonsurgical Interventional Spine Pain Procedures

Nonsurgical interventional spine pain procedures provide an additional treatment option for lower back pain at the traditional bifurcation of conversative vs. operative management. Transforaminal epidural steroid injections, radiofrequency ablations, intrathecal drug delivery, and spinal cord stimulation were found to be effective and safe techniques when applied to their specific indication. Thermal annuloplasty and minimally invasive lumbar decompression showed mixed support. Discography, sacroiliac joint injections, and spinous process spacers lacked sufficient evidence to support efficacy. Medial branch blocks and facet joint injections were found to be useful diagnostic tools.

Immunomodulation: The next target of mesenchymal stem cell-derived exosomes in the context of ischemic stroke.

Ischemic stroke (IS) is the most prevalent form of brain disease, characterized by high morbidity, disability, and mortality. However, there is still a lack of ideal prevention and treatment measures in clinical practice. Notably, the transplantation therapy of mesenchymal stem cells (MSCs) has been a hot research topic in stroke. Nevertheless, there are risks associated with this cell therapy, including tumor formation, coagulation dysfunction, and vascular occlusion. Also, a growing number of studies suggest that the therapeutic effect after transplantation of MSCs is mainly attributed to MSC-derived exosomes (MSC-Exos). And this cell-free mediated therapy appears to circumvent many risks and difficulties when compared to cell therapy, and it may be the most promising new strategy for treating stroke as stem cell replacement therapy. Studies suggest that suppressing inflammation via modulation of the immune response is an additional treatment option for IS. Intriguingly, MSC-Exos mediates the inflammatory immune response following IS by modulating the central nervous system, the peripheral immune system, and immunomodulatory molecules, thereby promoting neurofunctional recovery after stroke. Thus, this paper reviews the role, potential mechanisms, and therapeutic potential of MSC-Exos in post-IS inflammation in order to identify new research targets.

A shortened whole brain radiation therapy protocol for meningoencephalitis of unknown origin in dogs.

A variety of treatment options have been described for canine meningoencephalitis of unknown origin (MUO). Few studies focused on radiation therapy as a second line immunomodulating treatment, implicating its effective use. However, a standard radiation therapy protocol is lacking, and further research will help to evaluate the effect of different dose regimens. Ten dogs diagnosed with MUO based on MRI and CSF findings were prospectively enrolled. The dogs were treated with a shortened whole brain radiation therapy protocol (5 × 4 Gy) in combination with prednisolone. Neurologic changes were quantified using an established scoring scheme. Follow-up MRI and CSF examination was scheduled three months after radiation therapy. Overall survival and time to progression were calculated. Histopathology of the brain was performed in case of death. Seven dogs were diagnosed de novo and three had a history of relapsing MUO. Neurological status improved in all 10 dogs during radiation therapy, with 4/10 returning to normal shortly after radiation therapy. Three dogs died within the first three months after radiation therapy. At follow-up MRI lesions completely resolved in two dogs, partially resolved in five dogs, and progressed in one dog. After follow-up MRI, dogs were further treated with prednisolone monotherapy (two dogs) and additional immunosuppressant drugs (five dogs). Overall, four dogs showed disease progression, with a mean time to progression of 691 days (95%CI: 396-987) and mean overall survival for all dogs was 723 days (95%CI: 436-1011) (both medians not reached). Histopathology confirmed MUO in three dogs but was suggestive for oligodendroglioma in one dog. Radiation induced side effects were not seen. Shortened whole-brain radiation therapy could be an additional treatment option for MUO in conjunction to prednisolone, specifically for cases that require rapid relief of symptoms and with relapsing history.

Identification of a Synthetic Polyhydroxyphenolic Resveratrol Analogue, 3,3',4,4',5,5'-Hexahydroxy-trans-Stilbene with Anti-SARS-CoV-2 Activity.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has been causing the COVID-19 pandemic since December 2019, with over 600 million infected persons worldwide and over six million deaths. We investigated the anti-viral effects of polyphenolic green tea ingredients and the synthetic resveratrol analogue 3,3',4,4',5,5'-hexahydroxy-trans-stilbene (HHS), a compound with antioxidant, antitumor and anti-HIV properties. In the TCID50 assay, four out of nine green tea constituents showed minor to modest cell protective effects, whereas HHS demonstrated the highest reduction (1103-fold) of the TCID50, indicating pronounced inhibition of virus replication. HHS was also a highly effective inhibitor of SARS-CoV-2 proliferation in VeroE6 cells with an IC50 value of 31.1 µM. HSS also inhibited the binding of the receptor-binding domain (RBD) of the spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor (RBD-ACE2) binding with 29% at 100 µM and with 9.2% at 50 µM indicating that the SARS-CoV-2 inhibitory effect might at least in part be attributed to the inhibition of virus binding to ACE2. Based on the chemical similarity to other polyphenols, the oral bioavailability of HHS is likely also very low, resulting in blood levels far below the inhibitory concentration of EGCG against SARS-CoV-2 observed in vitro. However, administration of HHS topically as a nose or throat spray would increase concentrations several-fold above the minimal inhibitory concentration (MIC) in the mucosa and might reduce virus load when administered soon after infection. Due to these promising tissue culture results, further preclinical and clinical studies are warranted to develop HHS as an additional treatment option for SARS-CoV-2 infection to complement vaccines, which is and will be the main pillar to combat the COVID-19 pandemic.

Case report: Sustained complete remission with ivosidenib in a patient with relapsed, IDH1-mutated acute leukemia

Older patients with acute lymphoblastic leukemia (ALL) have a poor prognosis, with a 5-year overall survival rate of only 10%–20%. This is attributable to patient comorbidities, poor performance status, and high-risk disease biology. The prognosis for patients with relapsed/refractory (R/R) disease remains poor, particularly for patients who are not candidates for therapies targeting CD19 or CD22. Additional treatment options are needed for these patient populations. The patient presented here is a 76-year-old man diagnosed with precursor B-cell ALL with aberrant expression of myeloid markers and lacking significant CD19 or CD22 expression. A 3-year remission was achieved with one cycle of CVP (cyclophosphamide, vincristine, and prednisone) followed by 22 months of maintenance DOMP (dexamethasone, vincristine, methotrexate, and 6-mercaptopurine) prior to relapse. He was then treated with one cycle of salvage CVP, which was complicated by a stroke resulting in hemiparesis. Next-generation sequencing (NGS) was performed on the relapsed bone marrow, which revealed the presence of an R132H mutation in the isocitrate dehydrogenase 1 (IDH1) gene. He was subsequently treated with the IDH1 inhibitor ivosidenib and remained in a second remission for nearly 1 year. IDH1 mutations are present in up to 14% of acute myeloid leukemia (AML) cases but are also seen more rarely in ALL, particularly in cases involving aberrant expression of myeloid markers. Ivosidenib has demonstrated efficacy in patients with IDH1-mutated AML but has not been extensively studied in other hematologic malignancies. This case demonstrates the role of NGS in revealing treatment options in patients with otherwise limited available therapies.

Anterior gradient 2 induces resistance to sorafenib via endoplasmic reticulum stress regulation in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) accounts for almost 80% of all liver cancer cases and is the sixth most common cancer and the second most common cause of cancer-related death worldwide. The survival rate of sorafenib-treated advanced HCC patients is still unsatisfactory. Unfortunately, no useful biomarkers have been verified to predict sorafenib efficacy in HCC.ResultsWe assessed a sorafenib resistance-related microarray dataset and found that anterior gradient 2 (AGR2) is highly associated with overall and recurrence-free survival and with several clinical parameters in HCC. However, the mechanisms underlying the role of AGR2 in sorafenib resistance and HCC progression remain unknown. We found that sorafenib induces AGR2 secretion via posttranslational modification and that AGR2 plays a critical role in sorafenib-regulated cell viability and endoplasmic reticulum (ER) stress and induces apoptosis in sorafenib-sensitive cells. In sorafenib-sensitive cells, sorafenib downregulates intracellular AGR2 and conversely induces AGR2 secretion, which suppresses its regulation of ER stress and cell survival. In contrast, AGR2 is highly intracellularly expressed in sorafenib-resistant cells, which supports ER homeostasis and cell survival. We suggest that AGR2 regulates ER stress to influence HCC progression and sorafenib resistance.ConclusionsThis is the first study to report that AGR2 can modulate ER homeostasis via the IRE1α-XBP1 cascade to regulate HCC progression and sorafenib resistance. Elucidation of the predictive value of AGR2 and its molecular and cellular mechanisms in sorafenib resistance could provide additional options for HCC treatment.

The availability of gonadotropin therapy from FDA-approved pharmacies for men with hypogonadism and infertility.

Recent changes to the Biologics Price Competition and Innovation Act of 2009 have created barriers to accessing therapy for men utilizing gonadotropins for hypogonadism and infertility. In this study we sought to investigate ways to decrease disparities in the treatment of male hypogonadism by increasing access to gonadotropin therapy by identifying 503b outsourcing pharmacies which currently provide gonadotropin therapy. A review of 503b compounding pharmacies was performed using the online published registry available from the US Food and Drug Administration (FDA). Each pharmacy was contacted regarding their ability to provide gonadotropin therapy. Pharmacies were also queried regarding the impact of FDA-related legal changes and cost considerations. The study outcomes were the number and location of FDA-approved 503b compounding pharmacies supplying human chorionic gonadotrophin (hCG) and/or follicle-stimulating hormone (FSH) for the treatment of male hypogonadism and infertility. The 81 503b-compounding pharmacies approved by the FDA to produce hCG and FSH therapy were identified using the FDA registry. Seventy-five of the 81 pharmacies responded to the survey (response rate92.6%). Of the contacted pharmacies, 5 provided hCG (6.67%). Of the pharmacies offering compounded hCG, 4 offered FSH. No additional pharmacies offered compounded FSH. Eight pharmacies had previously provided hCG and FSH. Six of the 8 pharmacies that stopped making hCG and FSH cited the 2020 FDA mandate as the reason for halting compounding services. Of the 75 pharmacies that responded, only 1 pharmacy provided the cost for FSH ($287 per 100-IU vial), and 3 pharmacies provided the cost for hCG ($50-$83 per 10 000-IU vial). There are few FDA-approved outsourcing pharmacies currently providing male gonadotropin therapy, and increasing awareness of these pharmacies may decrease barriers to care for patients with male hypogonadism and infertility. The strengths of this article are the clinical utility of the data presented, as this article may serve as a tool for clinicians to increase patient access to therapy. All FDA-approved 503b outsourcing pharmacies were contacted, and 92.6% participated in this project. Limitations of this article were the following: no non-FDA-approved compounding pharmacies such as 503a pharmacies were contacted, participant-reported outcomes were utilized, and only 3 contacted outsourcing pharmacies provided a cost for FSH or hCG, allowing for an unknown degree of cost variability between outsourcing pharmacies. There currently exists limited access to FDA-approved compounded gonadotropin therapies for hypogonadism and male infertility, and these results demonstrate the barriers to hCG and FSH access and the need for additional treatment options for this vulnerable patient population.

Precision Oncology in Pancreatic Cancer: Experiences and Challenges of the CCCMunichLMU Molecular Tumor Board.

In pancreatic cancer, systemic treatment options in addition to chemotherapy remain scarce, and so far only a small proportion of patients benefit from targeted therapies. The patients with pancreatic cancer discussed in the CCCMunichLMU Molecular Tumor Board were reviewed to gain a better real-world understanding of the challenges and chances of precision oncology in this hard-to-treat cancer. Patients with pancreatic cancer who received comprehensive genomic profiling and were discussed in the interdisciplinary Molecular Tumor Board between May 2017 and July 2022 were included. These patients' medical charts, comprehensive genomic profiling results, and Molecular Tumor Board recommendations were analyzed in this retrospective cohort study. Molecular profiles of 165 patients with pancreatic cancer were discussed in the Molecular Tumor Board. In the 149 cases where comprehensive genomic profiling was successful, KRAS mutations were detected in 87.9%, TP53 in 53.0%, and CDKN2A in 14.1%. 33.3% of KRAS wild-type patients harbored targetable mutations, while these were only found in 19.1% of patients with the KRAS mutation; however, this difference was not statistically significant. 63.8% of patients with successful testing received a targeted treatment recommendation by the Molecular Tumor Board; however, only 3.2% of these were put into practice. Compared to a historic cohort of patients with pancreatic cancer with synchronous metastatic disease diagnosed between 2010 and 2017, the patients from the pancreatic cancer cohort with synchronous metastatic disease had a longer survival. This single-center experience emphasizes the challenges of targeted treatment in pancreatic cancer. Very few patients ultimately received the recommended therapies, highlighting the need for more and better targeted treatment options in pancreatic cancer, early comprehensive genomic profiling to allow sufficient time to put Molecular Tumor Board recommendations into practice, and close cooperation with clinical trial units to give patients access to otherwise not available targeted treatments.

Delivery of neutrophil membrane encapsulated non-steroidal anti-inflammatory drugs by degradable biopolymer microneedle patch for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a common chronic autoimmune disease and eventually ends in severe disability and death. RA has no cure, but there are some treatments for decreasing the severity of various symptoms. For example, pain management of RA by non-steroidal anti-inflammatory drugs (NSAIDs), neutralization of the inflammatory cytokines (or block their functions) of RA by specific biologics. However, the clinical benefit is limited due to their low permeability and poor bioavailability. Meanwhile, the system toxicity for long-term use of NSAIDs is another focal issue. Herein, degradable biopolymer microneedle patch was designed and synthesized. In this dual drug delivery patch, NSAIDs were encapsulated by polymeric nanoparticles, which were coated by the neutrophil membrane, followed by loaded into the microneedle patch for local transdermal delivery. When applied to the murine models, the microneedle patch gradually dissolves and releases the contained nanoparticles. Coating of neutrophil membrane provides the nanosized NSAIDs with the capability of cytokine binding and inflammatory joint tropism. Based on inflammatory microenvironment regulation by cytokine absorption and cyclooxygenase-2 inhibition, the microneedle shows a significant local anti-inflammatory therapeutic effect on mouse model of collagen-induced arthritis and rat model of adjuvant-induced arthritis. Further development based on this advanced strategy may provide additional therapeutic options for RA treatment.

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence.

Abemaciclib [Verzenio® (USA) or Verzenios® (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.

Study of real-world treatment patterns and adherence to bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with high-risk non-muscle invasive bladder cancer (NMIBC).

470 Background: Intravesical BCG is considered a first-line (1L) treatment for high-risk NMIBC patients. Since the presence of carcinoma in situ (CIS) in NMIBC is associated with increased disease progression rates and poor clinical outcomes, BCG is prioritized in clinical guidelines for NMIBC patients with CIS. However, BCG’s US shortage may negatively affect clinical outcomes in patients. This study evaluated the adequacy of BCG treatment patterns among NMIBC patients, including a subgroup with CIS. Methods: Adults with NMIBC treated with BCG were selected from de-identified IBM MarketScan Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Treatment patterns were assessed from the first BCG claim (triggering the start of 1L treatment) until the end of the patient’s observation. Consistent with real-world literature, adequate BCG induction was defined as ≥5 BCG claims within 70 days of the first BCG claim whereas adequate BCG induction and maintenance was defined as ≥7 BCG claims within 274 days of the first BCG claim. Proportions of patients with adequate BCG induction and maintenance were compared between CIS subgroup and overall NMIBC cohorts using chi square tests. Results: Of 5,803 NMIBC patients treated with 1L BCG, 1,182 (20.4%) had documentation of CIS. Overall and CIS cohorts had similar mean age (67 years; range 18-101 years). After 1L BCG, 56.6% and 71.8% of the overall and CIS cohorts had another treatment (P<.001; table). While 86.9% and 90.0% of the overall and CIS cohorts had adequate BCG induction (P=0.003), only 41.5% and 50.8% had adequate BCG maintenance (P<.001). More patients in the CIS versus overall cohort had a cystectomy (13.9% vs 9.7%; P<.001). Conclusions: In this study, most NMIBC patients treated with BCG received adequate induction; however, BCG maintenance was inadequate and most patients had another treatment following 1L BCG. Patients with CIS were more likely to have cystectomy after BCG, suggesting higher risk of progression in this subgroup. Results of this study further emphasize a need for additional available treatment options that are safe, efficacious, and tolerable. [Table: see text]

A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases.

TPS745 Background: A SEER analysis from 2010 to 2013 demonstrated that the incidence of brain metastases(mets) at the diagnosis of renal cell carcinoma(RCC) is 1.51%, and around 12% of patients(pts) with advanced RCC (aRCC) also had mets to the brain. Brain mets confer a poor prognosis. Local management strategies for brain mets from RCC include surgical resection, stereotactic radiosurgery and whole brain radiation therapy. Although systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is a potent small molecule inhibitor of multiple tyrosine kinases that was approved by FDA for pts with aRCC alone or in combination with nivolumab. Cabozantinib has demonstrated activity in patients with intracranial tumors. A phase III trial (COSMIC-313) recently evaluated cabozantinib in combination with nivolumab and ipilimumab compared to nivolumab plus ipilimumab and demonstrated significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. The combination was found to be safe as frontline systemic treatment. The role of this combination in patients with aRCC with brain mets remains undefined. As such, we propose a study to assess the safety and efficacy of cabozantinib in combination with nivolumab/ipilimumab in RCC pts with untreated brain mets. We believe the results from this trial could provide additional treatment options for pts with RCC brain mets who are typically excluded from clinical trials. Methods: This is a phase II study to assess the safety and efficacy of the combination of nivolumab with ipilimumab and cabozantinib in pts with untreated brain mets from RCC until disease progression or intolerable toxicities or patient withdrawal. Planned accrual is 40 pts. Pts will be treated with nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily. Then pts will be treated with nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until progression or intolerable toxicities or patient’s withdrawal. A lead-in group of 6 pts will be closely monitored for dose limiting toxicities(DLT). If stopping criteria (>3 patients develop DLTs) is met, then treatment will be switched to nivolumab plus cabozantinib omitting ipilimumab. The primary objective is intracranial progression free survival(PFS). Secondary objectives include intracranial safety, objective response rate (intracranial + extracranial) by modified RECIST v1.1 and RECIST v1.1, extracranial PFS and overall survival. This phase II trial is currently enrolling pts. Clinical trial information: NCT05048212 .

Evaluation of effectiveness of combined supportive treatment for paronychia and pyogenic granulomas, associated with targeted anticancer therapy

BACKGROUND: Paronychia and pyogenic granulomas occur in 1050% of patients treated with epidermal growth receptor (EGFR) inhibitors. Supportive therapy for periungual lesions is challenging, since these adverse reactions are prone to torpidity and frequent relapses.
 AIM: to evaluate the effectiveness of supportive treatment for paronychia and pyogenic granulomas ― dermatologic adverse events of EGFR inhibitors, with a combined cream with betamethasone dipropionate, clotrimazole, gentamicin, and betaxolol solution.
 MATERIALS AND METHODS: 16 patients with paronychia and pyogenic granulomas associated with EGFR inhibitor therapy were included in a 12-week open-label prospective study. Paronychia and pyogenic granulomas severity assessment was performed with the NCI-CTCAE v. 5.0, a developed 10-point scale. The intensity of pain was assessed with a visual-analogue scale (VAS). The quality of life was assessed with the Dermatology Life Quality Index (DLQI).
 RESULTS: A significant improvement of all parameters (p 0.05) was evaluated from week 1, indicating the effective reduction of dermatologic adverse event objective and subjective symptoms, improvement of patients quality of life. By the end of the study, 37.5% of patients had complete resolution of lesions, 62.5% of patients had minimal residual erythema. Decrease of pain sensation in the affected periungual folds was observed throughout the study (p 0.05). DLQI score indicated the "small effect" of paronychia and pyogenic granulomas on patients life by the end of the study.
 CONCLUSIONS: Supportive treatment of paronychia and pyogenic granulomas with a combined cream with betamethasone dipropionate, clotrimazole and gentamicin and a betaxolol 0.25% solution is effective in the management of paronychia and pyogenic granulomas objective and subjective symptoms, has a high tolerability, allows to improve patients quality of life and continue targeted therapy without dose reduction. Long-term maintenance of pain sensation after paronychia and pyogenic granulomas resolution underlines the need for additional treatment options that will improve the effectiveness of pain management.