Browsing by Subject "Targeted therapy"

Now showing 1 - 10 of 25
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    A phase II trial of sitravatinib + nivolumab after progression on immune checkpoint inhibitor in patients with metastatic clear cell RCC
    (Oxford University Press, 2025) Hahn, Andrew W.; Adra, Nabil; Vaishampayan, Ulka; Xiao, Lianchun; Dizman, Nazli; Yuan, Ying; Mukhida, Sagar S.; Campbell, Matthew T.; Gao, Jianjun; Zurita, Amado J.; Jonasch, Eric; Tannir, Nizar M.; Shah, Amishi Y.; Msaouel, Pavlos; Medicine, School of Medicine
    Background: Sitravatinib, an oral multi-kinase inhibitor targeting VEGFR, TAM, and MET, has been shown to resensitize the tumor microenvironment to immune checkpoint inhibitors (ICI) by reducing immune-suppressive myeloid cells in metastatic clear cell RCC (ccRCC). ICI is the standard first-line (1L) treatment of metastatic ccRCC, and there is unmet need for improved treatment outcomes after progression on ICI. We hypothesized that sitravatinib plus nivolumab would revert an immunosuppressive tumor microenvironment (TME) to improve clinical outcomes. Methods: In this investigator-initiated, phase II, multicenter trial (NCT04904302), patients with progressive metastatic ccRCC after 1-2 lines of treatment were enrolled into 3 cohorts: (1) 1L nivolumab + ipilimumab, (2) 1L pembrolizumab + axitinib, (3) prior cabozantinib or lenvatinib and ICI. Starting dose of sitravatinib was 100 mg PO daily and nivolumab was 480 mg IV every 4 weeks. The co-primary endpoints were objective response rate (ORR) and disease control rate (DCR) at 24 weeks. The study was designed to enroll 88 patients with an interim analysis for futility in each cohort using a BOP2 design, but it was terminated early due to discontinuation of sitravatinib development. Results: Fourteen patients were enrolled with 2 in cohort A, 6 in cohort B, and 6 in cohort C. Across all cohorts, the ORR was 15.4% (2/13, 1 not evaluable) and DCR at 24 weeks was 35.7% (5/14). DCR at 24 months was 63% for Cohort A + B and 0% for Cohort C. Median progression free survival was 5.5 mo [95% CI 3.8-not reached (NR)], and median overall survival was 13.3 mo (95% CI 8.77-NR). Six patients (42.9%) experienced a grade 3-4 adverse event (AE) and 2 patients (14.3%) experienced an immune-mediated AE. Conclusion: In this small phase 2 trial with limited sample size due to early termination, sitravatinib plus nivolumab demonstrated a manageable safety profile and produced modest clinical benefit. The observed responses occurred in patients who did not receive prior treatment with cabozantinib or lenvatinib.
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    A Review of Current and Pipeline Drugs for Treatment of Melanoma
    (MDPI, 2024-02-07) Natarelli, Nicole; Aleman, Sarah J.; Mark, Isabella M.; Tran, Jasmine T.; Kwak, Sean; Botto, Elizabeth; Aflatooni, Shaliz; Diaz, Michael J.; Lipner, Shari R.; Medicine, School of Medicine
    Malignant melanoma is the most aggressive form of skin cancer. Standard treatment options include surgery, radiation therapy, systemic chemotherapy, targeted therapy, and immunotherapy. Combining these modalities often yields better responses. Surgery is suitable for localized cases, sometimes involving lymph node dissection and biopsy, to assess the spread of the disease. Radiation therapy may be sometimes used as a standalone treatment or following surgical excision. Systemic chemotherapy, while having low response rates, is utilized as part of combination treatments or when other methods fail. The development of resistance to systemic chemotherapies and associated side effects have prompted further research and clinical trials for novel approaches. In the case of advanced-stage melanoma, a comprehensive approach may be necessary, incorporating targeted therapies and immunotherapies that demonstrate significant antitumor activity. Targeted therapies, including inhibitors targeting BRAF, MEK, c-KIT, and NRAS, are designed to block the specific molecules responsible for tumor growth. These therapies show promise, particularly in patients with corresponding mutations. Combination therapy, including BRAF and MEK inhibitors, has been evidenced to improve progression-free survival; however, concerns about resistance and cutaneous toxicities highlight the need for close monitoring. Immunotherapies, leveraging tumor-infiltrating lymphocytes and CAR T cells, enhance immune responses. Lifileucel, an FDA-approved tumor-infiltrating lymphocyte therapy, has demonstrated improved response rates in advanced-stage melanoma. Ongoing trials continue to explore the efficacy of CAR T-cell therapy for advanced melanoma. Checkpoint inhibitors targeting CTLA-4 and PD-1 have enhanced outcomes. Emerging IL-2 therapies boost dendritic cells, enhancing anticancer immunity. Oncolytic virus therapy, approved for advanced melanoma, augments treatment efficacy in combination approaches. While immunotherapy has significantly advanced melanoma treatment, its success varies, prompting research into new drugs and factors influencing outcomes. This review provides insights into current melanoma treatments and recent therapeutic advances.
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    Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy
    (Taylor & Francis, 2021) Baiocchi, Leonardo; Sato, Keisaku; Ekser, Burcin; Kennedy, Lindsey; Francis, Heather; Ceci, Ludovica; Lenci, Ilaria; Alvaro, Domenico; Franchitto, Antonio; Onori, Paolo; Gaudio, Eugenio; Wu, Chaodong; Chakraborty, Sanjukta; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    Introduction: Cholangiocarcinoma (CCA) is a devastating liver tumor with a poor prognosis. While less than 50% of patients with CCA may benefit from surgical resection, the rest undergoes chemotherapy with disappointing results (mean survival <2 years). Alternative pharmacological treatments are needed to improve the outcomes in patients with CCA. Areas covered: In this review, we discuss CCA-related: i) experimental systems used in preclinical studies; ii) pharmacological targets identified by genetic analysis; iii) results obtained in preliminary trials in human with their pros and cons; and iv) possible targeting of endocrinal modulation. A PubMed bibliographic search matching the term “cholangiocarcinoma” with “experimental model”, “preclinical model”, “genetic target”, “targeted therapy”, “clinical trial” or “translational research” was conducted and manuscripts published between 2010 and 2020 were retrieved for reading and reviewing. Expert opinion: Several factors contribute to the translational gap between bench research and clinical practice in CCA. The tumor heterogeneity, lack of a preclinical model recapitulating the different features of CCA, and difficult patient enrollment in clinical trials are elements to consider for basic and clinical research in CCA. Establishment of international networks formed by experts in the field of CCA may improve future research and its translational findings on patients.
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    Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy
    (Frontiers Media, 2021-10-18) Elbanna, May; Chowdhury, Nayela N.; Rhome, Ryan; Fishel, Melissa L.; Radiation Oncology, School of Medicine
    In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ''one size fits all'' paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.
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    Contemporary management of muscle-invasive bladder cancer
    (Taylor & Francis, 2012) Dall’Era, Marc A.; Cheng, Liang; Pan, Chong-Xian; Pathology and Laboratory Medicine, School of Medicine
    The current standard treatment for muscle-invasive nonmetastatic bladder cancer is neoadjuvant platinum-based chemotherapy followed by radical cystectomy. However, neoadjuvant chemotherapy is not widely accepted even with level 1 evidence. Adjuvant chemotherapy should be discussed if patients have not received neoadjuvant chemotherapy before surgery and have high-risk pathologic features. Although not considered standard of care, bladder-sparing therapy can be considered for highly selected patients and for those medically unfit for surgery. Even though there are no level 1 data, the treatment outcomes for highly select patients given bladder-sparing therapy appear promising, with many patients retaining a functional bladder. Personalized chemotherapy is currently being actively pursued to target the underlying molecular changes and tailor to individual needs.
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    Corrigendum: Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma
    (Frontiers Media, 2023-11-15) Nguyen, Hong Phuong; Le, Anh Quynh; Liu, Enze; Cesarano, Annamaria; DiMeo, Francesco; Perna, Fabiana; Kapur, Reuben; Walker, Brian A.; Tran, Ngoc Tung; Pediatrics, School of Medicine
    [This corrects the article DOI: 10.3389/fimmu.2023.1239614.].
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    Current Landscape of Targeted Therapies for Hormone-Receptor Positive, HER2 Negative Metastatic Breast Cancer
    (Frontiers, 2018-08-10) Ballinger, Tarah J.; Meier, Jason B.; Jansen, Valerie; Medicine, School of Medicine
    The majority of deaths from MBC are in patients with hormone receptor (HR) positive, HER2 negative disease. Endocrine therapy (ET) remains the backbone of treatment in these cases, improving survival and quality of life. However, treatment can lose effectiveness due to primary or acquired endocrine resistance. Analysis of mechanisms of ET resistance has led to the development of a new generation of targeted therapies for advanced breast cancer. In addition to anti-estrogen therapy with selective estrogen receptor modulators, aromatase inhibitors, and/or selective estrogen receptor degraders, combinations with cyclin dependent kinase (CDK) 4/6 inhibitors have led to substantial progression free survival (PFS) improvements in the first and second line settings. While the PI3K/AKT/mTOR pathway is known to be an important growth pathway in HR positive breast cancer, PI3K inhibitors have been disappointing due to modest effect sizes and significant toxicity. The mTOR inhibitor everolimus significantly improves progression free survival when added to ET, and recent studies have improved supportive care allowing less toxicity. While these combination targeted therapies improve outcomes and often delay initiation of chemotherapy, long term overall survival data are lacking and data for the ideal strategy for sequencing these agents remains unclear. Ongoing research evaluating potential biomarkers and mechanisms of resistance is anticipated to continue to improve outcomes for patients with HR positive metastatic breast cancer. In this review, we will discuss management and ongoing challenges in the treatment of advanced HR positive, HER2 negative breast cancer, highlighting single agent and combination endocrine therapies, targeted therapies including palbociclib, ribociclib, abemaciclib, and everolimus, and sequencing of therapies in the clinic.
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    Current Treatment Approaches and Global Consensus Guidelines for Brain Metastases in Melanoma
    (Frontiers Media, 2022-05-05) Tan, Xiang-Lin; Le, Amy; Lam, Fred C.; Scherrer, Emilie; Kerr, Robert G.; Lau, Anthony C.; Han, Jiali; Jiang, Ruixuan; Diede, Scott J.; Shui, Irene M.; Graduate Medical Education, School of Medicine
    Background: Up to 60% of melanoma patients develop melanoma brain metastases (MBM), which traditionally have a poor diagnosis. Current treatment strategies include immunotherapies (IO), targeted therapies (TT), and stereotactic radiosurgery (SRS), but there is considerable heterogeneity across worldwide consensus guidelines. Objective: To summarize current treatments and compare worldwide guidelines for the treatment of MBM. Methods: Review of global consensus treatment guidelines for MBM patients. Results: Substantial evidence supported that concurrent IO or TT plus SRS improves progression-free survival (PFS) and overall survival (OS). Guidelines are inconsistent with regards to recommendations for surgical resection of MBM, since surgical resection of symptomatic lesions alleviates neurological symptoms but does not improve OS. Whole-brain radiation therapy is not recommended by all guidelines due to negative effects on neurocognition but can be offered in rare palliative scenarios. Conclusion: Worldwide consensus guidelines consistently recommend up-front combination IO or TT with or without SRS for the treatment of MBM.
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    Highly variable biodistribution of 68Ga labeled somatostatin analogues 68Ga-DOTA-NOC and 68Ga-DOTA-TATE in neuroendocrine tumors: clinical implications for somatostatin receptor directed PET/CT
    (AME, 2022) Cheng, Monica; Tann, Mark; Radiology and Imaging Sciences, School of Medicine
    Background: Somatostatin receptor (SSTR)-targeted positron emission tomography/computed tomography (PET/CT) imaging has risen to the forefront for neuroendocrine tumor (NET) detection and management, yet the variability of significant uptake variability (SUV) as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored. Methods: We assess the reproducibility and interscan variability of SUV metrics of normal tissue and NET in serial 68Ga-DOTA-NOC and 68Ga-DOTA-TATE PET imaging to clinically monitor disease state. Eighty-one patients were enrolled in this retrospective study. Results: Both primary and metastatic hepatic lesions demonstrated SUV (SUVmean 16.5±8.0). The median SUVmean was 16 for the spleen, 9.7 for the pituitary, 12.6 for the adrenal glands, and 4.8 for the liver. The normal pituitary gland demonstrates focal homogenous uptake with SUVmax range of 4.5-23. The adrenal gland showed uptake with SUVmax range of 4.1-29.4, which is more than two times greater than liver uptake (SUVmean range, 2.3-12.4). Highest physiological uptake seen in the spleen (average SUVmean of 17.3, range of 5.4-34.4). Conclusions: The highly variable nature of regional SUVmean and SUVmax in both physiologic tissue and lesions suggests the need for incorporation of more reliable quantitative measures for clinical decision making.
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    Identifying therapeutic targets in gastric cancer: the current status and future direction
    (Oxford University Press, 2016-01) Yu, Beiqin; Xie, Jingwu; Department of Pediatrics, IU School of Medicine
    Gastric cancer is the third leading cause of cancer-related death worldwide. Our basic understanding of gastric cancer biology falls behind that of many other cancer types. Current standard treatment options for gastric cancer have not changed for the last 20 years. Thus, there is an urgent need to establish novel strategies to treat this deadly cancer. Successful clinical trials with Gleevec in CML and gastrointestinal stromal tumors have set up an example for targeted therapy of cancer. In this review, we will summarize major progress in classification, therapeutic options of gastric cancer. We will also discuss molecular mechanisms for drug resistance in gastric cancer. In addition, we will attempt to propose potential future directions in gastric cancer biology and drug targets.