Treatment Options For Renal Cell Carcinoma Research Articles

Enhanced synergy of pacritinib with temsirolimus and sunitinib in preclinical renal cell carcinoma model by targeting JAK2/STAT pathway

Pacritinib is an oral medication that inhibits several kinases including JAK2, FLT3, IRAK and STAT3. It has been recently approved to treat patients with thrombocytopenia and myelofibrosis. Studies are currently exploring the potential use of pacritinib in treating other types of cancer such as leukaemia, breast cancer and prostate cancer. Our study aimed to investigate the effects of pacritinib alone and its combination with standard of care in renal cell carcinoma (RCC). We showed that pacritinib dose-dependently decreased viability of RCC cells, with IC50 at nanomolar or low micromolar concentration rage. Pacritinib inhibited cell proliferation, decreased colony formation, and increased apoptosis. Interestingly, pacritinib exhibited synergistic effects when combined with temsirolimus and sunitinib, but antagonistic effects when combined with doxorubicin, in a panel of RCC cell lines. We also confirmed that the combination of pacritinib with temsirolimus and sunitinib resulted in synergistic effects in RCC mouse models, with complete inhibition of tumour growth throughout the treatment period. Mechanistic studies indicated that the inhibition of JAK2, but not IRAK, was the main contributor to the anti-RCC activity of pacritinib. Our study is the first to demonstrate that pacritinib shows promise as a treatment option for RCC and underscores the therapeutic potential of targeting the JAK2/STAT signalling pathway in RCC.

Plain language summary looking at how long side effects last after treatment with axitinib is stopped in people with advanced renal cell carcinoma.

Axitinib is a medication that stops cancer cell growth by depriving the cancer cell of the nutrients and oxygen that it needs. Axitinib is used to treat advanced renal cell carcinoma (RCC), which is a type of kidney cancer that has spread within or beyond the kidney. Axitinib has been approved for the treatment of RCC as either a first treatment option or a second treatment option. It is used as a first treatment option for RCC when combined with a medication that reactivates the immune system (immunotherapy), either avelumab or pembrolizumab. If the advanced RCC starts growing again it can be used as a second treatment option where it is taken by itself. It is essential to conduct studies to assess how well the drug works and whether it has any side effects in order to understand whether it is safe to give to people. This summary reports the combined results of 5 studies and looks at how long side effects last after treatment is temporarily stopped. Researchers found that side effects generally got better in 3days or less after people stopped taking axitinib on its own. The time it took for side effects to get better was generally shorter than for other similar drugs or combinations of axitinib and immunotherapy. The results of individual studies may vary from these 5 combined study results. Three of the 5 studies were ongoing at the time of this analysis and the final outcomes of those studies may differ from those described in this summary. The purpose of this plain language summary is to help you understand the findings from recent research. Health professionals should make treatment decisions based on all available evidence. Clinical Trial Registration: NCT00678392, NCT00920816, NCT02493751, NCT02684006, NCT02853331 (ClinicalTrials.gov).

Cannabidiol Enhances Sunitinib Effect in Human Renal Cell Carcinoma by Inducing Apoptosis and Inhibiting Stat3 Signaling Pathway

Background: Renal cell carcinoma (RCC) is considered to be the most frequent form of kidney cancer affecting both men and women worldwide. Monotherapy is not always effective and often results in resistance. Aim: To evaluate cannabidiol and sunitinib combination in human RCC using 786-O cells as an in vitro model. Study Design: Experimental study Place and duration of study: Dow International Medical College, Karachi from 15th November 2021 to 14th May 2022. Methodology: 786-O cells were culture and treated with sunitinib, cannabidiol and the combination of both and the growth inhibition was evaluated using MTT assay, while cell apoptosis was determine using flowcytometry. qPCR was used to analyze the expression of apoptotic genes and STAT3 in sunitinib and cannabidiol treated cells. Results: Sunitinib, cannabidiol and the combination of both drugs showed a dose dependent inhibition on growth of 786-O cells (p <0.001). The rate of apoptosis was 14.4% and 24.3% when treated with cannabidiol and sunitinib respectively. When the two drugs were combined, apoptosis was significantly increased to 50.3% (p <0.001). qPCR showed that cannabidiol enhanced sunitinib induced apoptosis by downregulating anti-apoptotic gene (Bcl-2) and upregulating pro-apoptotic gene (caspase-3 and -9) (p <0.001). Practical Implication Using single drug for treating RCC is not always effective and often results in resistance. Our study suggests that cannabidiol in combination with sunitinib may be a preferable chemotherapeutic option for treatment of RCC. Conclusion: Cannabidiol enhances sunitinib effect in inhibiting RCC and their combination achieved more strong inhibition than either drug alone. Keywords: Cannabidiol, Renal cell carcinoma, Sunitinib, Apoptosis, STAT3, qPCR

DC-CTL targeting carbonic anhydrase IX gene combined with iAPA therapy in the treatment of renal cell carcinoma

ABSTRACT Introduction To deliver specific antigens in tumor immunotherapy, tumor cell lysates are commonly used to sensitize dendritic cells (DCs). However, the lysates possess low immunogenicity and contain many types of non-tumor-related antigens, which may induce autoimmune diseases. Tumor antigen peptides can provide high specificity but are expensive and their short half-lives limit their clinical application. Methods In this study, we used adenovirus to transfer the carbonic anhydrase IX (CA9) gene into DCs to generate specificity to renal cell carcinoma (RCC) which is the most common space-occupying lesion in humans. Inhibition of antigen presentation attenuators (iAPA) technology was also used to enhance the DC delivery capacity. Finally, DCs were co-cultured with cytotoxic T-lymphocytes (CTLs) and the anti-tumor effects were evaluated. Results The results showed that the CA9-DC-CTLs possessed a high specificity to CA9-positive cells and showed stronger anti-tumor activity than GFP-DC-CTLs both in vitro and in vivo. Discussion These findings may suggest a novel treatment option for RCC.

An open-label phase II study comparing two doses of MK-6482 for the treatment of advanced renal cell carcinoma (RCC) following progression on prior systemic therapy.

TPS369 Background: Treatment options for RCC in the late-line setting after immunotherapy and vascular endothelial growth factor (VEGF)-targeted therapy are limited. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). The first-in-class small molecular HIF-2α inhibitor, MK-6482, recently showed promising antitumor activity in a cohort of heavily pretreated ccRCC patients (pts) and in pts with von Hippel-Lindau–disease-associated RCC for which the FDA granted Breakthrough Therapy Designation to MK-6482. Methods: This randomized, open-label, multicenter phase II trial will evaluate the efficacy and safety of 2 doses of MK-6482 in pts with advanced RCC who have experienced progression after prior systemic therapy (NCT04489771). Eligible pts are male or female aged ≥18 years with histologically confirmed locally advanced or metastatic ccRCC (measurable disease per RECIST v1.1) who have experienced progression after 1-3 prior systemic therapies comprising an anti-PD-1/L1 agent combined with a VEGF-targeted tyrosine kinase inhibitor (TKI) or an anti-cytotoxic T lymphocyte-associated antigen-4 agent and have undergone no more than 3 prior systemic regimens; and a Karnofsky Performance Scale ≥70. Treatment progression on anti-PD-1/L1 combination therapy was defined as pts who received at least 2 doses of anti-PD-1/L1 therapy and demonstrated radiographic disease progression as assessed by the investigator. Pts who have received prior treatment with MK-6482 or another HIF-2α inhibitor, and those requiring intermittent or chronic supplemental oxygen, or with a baseline hemoglobin less than 10 g/dL, a history of human immunodeficiency virus, hepatitis B or hepatitis C infection, or active central nervous system metastases will be excluded. Approximately 150 pts will be randomly assigned 1:1 to oral MK-6482 120 mg once daily (QD) or 200 mg QD; treatment will continue until progression, unacceptable toxicity, or withdrawal. Pts will be stratified by International Metastatic RCC Database Consortium prognostic scores (0, 1-2, 3-6) and the number of prior TKI-containing therapies (0, 1, or 2-3). Imaging with computed tomography or magnetic resonance imaging will be undertaken on Week 9 from the date of randomization, every 8 weeks through Week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. Safety will be analyzed using a tiered approach. This study is recruiting. Clinical trial information: NCT04489771 .

Transabdominal approach for renal cell carcinoma with supradiaphragmatic tumor thrombus: description of a modified technique and indications for treatment.

ObjectiveWe investigated the safety and effectiveness of a modified transabdominal approach for renal cell carcinoma (RCC) with a supradiaphragmatic inferior vena cava (IVC) tumor thrombus (TT).MethodsEight patients underwent radical nephrectomy with removal of a supradiaphragmatic IVC-TT through an abdominal incision using a transdiaphragmatic approach in Peking University Third Hospital from April 2015 to January 2018. We modified this technique using a Foley catheter balloon to avoid piggyback liver mobilization.ResultsAll patients underwent successful operations. The median operative time was 7 hours 23 minutes. The median estimated blood loss was 2963 mL. All patients received a blood transfusion with a median blood infusion volume of 2162 mL. Two patients with Budd–Chiari syndrome developed postoperative ascites and hydrothorax due to non-watertight repair of the diaphragm. During a follow-up of 11 to 44 months, only one patient died of liver metastasis and four patients developed distant metastasis without recurrence in the IVC.ConclusionsThe modified transabdominal approach described herein has an encouraging safety profile and provides a surgical option for treatment of RCC with a supradiaphragmatic IVC-TT. More evidence concerning the beneficial role of this procedure will be elucidated in further studies.

Radiation Therapy for Renal Cell Carcinoma

Radiation therapy (RT) has traditionally been disregarded in the primary or adjuvant treatment of renal cell carcinoma (RCC), but recent advances have necessitated a re-examination of the role radiation therapy may be able to play. The advent of stereotactic ablative radiotherapy (SABR), which allows for targeting of disease with higher doses in a shorter window of time, may open up new avenues for RT’s role in the treatment of RCC, a cancer with a relatively low alpha/beta ratio. Thus, this review examines both the history and future of RT in the treatment of RCC with an aim to expand the discussion on treatment options for RCC.

Quality of life outcomes in patients with localised renal cancer: a literature review

PurposePatients with localised renal cell carcinoma (RCC) can expect excellent oncologic outcomes. As such, there has been a shift towards maximising health-related quality of life (HRQoL). A greater understanding of HRQoL outcomes associated with different treatment options for RCC can facilitate patient-centred care, shared decision-making and enable cost utility analyses to guide health policies. The aim of this literature review was to evaluate the evidence regarding HRQoL following different management strategies for localised RCC.MethodsThree databases were searched to identify studies reporting HRQoL in patients with localised renal cancer, including Medline, the Tuft’s Medical Centre Cost Effectiveness Analysis registry and the EuroQol website.ResultsConsiderable methodological heterogeneity was noted. Laparoscopic nephrectomy was associated with significantly better short-term physical function compared to open surgery, although the effect on mental function was inconclusive. Nephron-sparing surgery was associated with better physical function compared to radical surgery. Patients’ perception of remaining renal function was a significant independent predictor of HRQoL, rather than surgery type. Tumour size, stage, post-operative complications, age, body mass index, occupational status, educational level and comorbidities were significant predictors of HRQoL. Only three studies were available regarding non-surgical management options and very little data were available regarding the impact of follow-up protocols and long-term effects of “cancer survivorship.”ConclusionThere is a need for validated and reproducible RCC-specific HRQoL instruments and standardisation amongst studies to enable comparisons. Increased awareness regarding determinants of poor HRQoL may enable high-risk patients to receive tailored support.

Bilateral Renal Masses with Different Histopathology Subtypes Treated by Laparoscopic Right Partial Nephrectomy and Bilateral Cryoablation- Results at 5 Years Follow-Up

We present the case of a 54 year old man with a synchronous mass on each kidney with different renal cell carcinoma (RCC) subtypes and a normal renal function. He categorically refused to undergo radical nephrectomy and open partial nephrectomies. He underwent a laparoscopic right partial nephrectomy and then percutaneous CTguided bilateral cryoablation. A second percutaneous CT-guided course of cryoablation on the right mass was performed at 6 months post cryoablation for recurrence. Both chest and abdomen CT-Scan at 60 months follow up did not reveal any local recurrence or distant metastasis. Although cryoablation is a feasible treatment option for RCC, the authors do not recommend it as a first line therapy in an otherwise healthy patient with normal renal function.

Treatment options for renal cell carcinoma in renal allografts: a case series from a single institution

Renal cell carcinoma (RCC) is more common in renal transplant and dialysis patients than the general population. However, RCC in transplanted kidneys is rare, and treatment has previously consisted of nephrectomy with a return to dialysis. There has been recent interest in nephron-sparing procedures as a treatment option for RCC in allograft kidneys in an effort to retain allograft function. Four patients with RCC in allograft kidneys were treated with nephrectomy, partial nephrectomy, or radiofrequency ablation. All of the patients are without evidence of recurrence of RCC after treatment. We found nephron-sparing procedures to be reasonable initial options in managing incidental RCCs diagnosed in functioning allografts to maintain an improved quality of life and avoid immediate dialysis compared with radical nephrectomy of a functioning allograft. However, in non-functioning renal allografts, radical nephrectomy may allow for a higher chance of cure without the loss of transplant function. Consequently, radical nephrectomy should be utilized whenever the allograft is non-functioning and the patient's surgical risk is not prohibitive.

Noninvasive Therapy of Incidental De Novo Renal Cell Carcinoma in a Kidney Allograft 12 Years After Transplantation: Report of a Case and Review of Literature

Background Immunosuppressive therapy increases the incidence of posttransplantation cancer. Primary renal cell carcinoma (RCC) represents 4.6% of all cancers in transplant recipients. The treatment options for RCC in a renal allograft include radical nephrectomy or nephron-sparing surgery. We report the case of a patient who underwent percutaneous radiofrequency ablation (RFA) of a RCC in the grafted kidney. Patient and Methods Twelve years after undergoing heterotopic, allogenic kidney transplantation, a de novo lesion was diagnosed in the upper pole of the kidney graft in a 77-year-old patient during routine duplex ultrasonography. The magnetic resonance image showed a spherical lesion of 17 mm in diameter, which undoubtedly showed radiological signs of a RCC. After adequately informing the patient about alternative treatment strategies and the associated risks, we made an interdisciplinary decision for a percutaneous RFA of the lesion. Results After the intervention, graft function remained unchanged and is still good at 6 months with no signs of local recurrence on follow-up MRI. A small coagulation defect at the site of the former lesion was the only morphological change. There was also no evidence of distant tumor spread. Conclusion Percutaneous RFA seems an acceptable, allograft-preserving treatment option associated with low morbidity and mortality for RCC in a renal allograft considering the significant risks associated with open partial nephrectomy in a kidney graft.