Phillip Kuo, MD, PhD, discusses the abstract, “[68Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: A VISION substudy,” which was presented at the 2022 ASCO Annual Meeting. 

 Dr. Kuo on PSMA-PET imaging biomarker research

In a recent interview, Sumanta K. Pal, MD, discussing promising clinical activity observed with the combination of the TKI cabozantinib (Cabometyx) and the immunotherapy atezolizumab (Tecentriq) in patients with metastatic urothelial carcinoma (UC) in the phase 1b COSMIC-021 clinical trial.

Pal, the lead author of the study and a professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope Comprehensive Cancer Center, shared results from the study at the 2022 ASCO annual meeting.

 The analysis included patients with inoperable locally advanced/metastatic UC who had transitional cell histology and an ECOG performance status of 0-1.

A total of 3 patients, 1 patient in cohort 3 and 2 in cohort 4, had complete responses, while partial responses were reached by 5 patients in cohort 3, 7 in cohort 4, and 3 patients in cohort 5, respectively. Further, the objective response rates seen in the trial were 20%, 30%, and 10%, and the disease control rates were 80%, 63%, and 61%.

What were the methods and design used within the COSMIC-021 study?

 The study is designed to test the principle that targeted therapy and immunotherapy have synergy. We started with dose escalation cohorts to make sure that cabozantinib and pembrolizumab are safe and combinable. Once we reached that we expanded to multiple different disease types where we thought that the combination would have activity. We've already published our results in kidney cancer. We have data that we've presented already in prostate cancer, [and] we have some data in platinum refractory bladder cancer. This represents some of the new data that we have for previously untreated bladder cancer.

To enroll in this study, many different tumor types are included, but in the specific cohorts that we focused on at ASCO 2022, again, patients had to have cisplatin-eligible status, cisplatin-ineligible status or have received a prior immune checkpoint inhibitor. These are patients with metastatic urothelial cancer, defined by the cisplatin eligibility as defined by conventional criteria.

Can you explain the safety and efficacy results seen in the trial?

In terms of efficacy, we determined that the response rate was 30%, 20%, and 10%, across the 3 cohorts ranging from cisplatin-eligible to ineligible to immune checkpoint inhibitor pretreated. In terms of some of the other data that we presented at the meeting, we have the median duration of response that we're reporting out within this cohort, which was 7.1 months amongst those patients that were cisplatin-ineligible, and 4.1 months in those that have received prior immune checkpoint inhibitors. This is what's really compelling. The median duration of response was not reached in those both patients that were cisplatin eligible. It is going to be interesting to see how that pans out.

We saw that the vast majority of patients of a cohort had some degree of tumor shrinkage with a combination irrespective of the cohort. In terms of progression free survival [PFS], the PFS in the cisplatin eligible cohort was 7.8 months. In the cisplatin ineligible cohort, it was 5.6 months. In terms of safety and tolerability, I thought that there weren't any unusual signals that you wouldn't expect from a caveat and that based immunotherapy combination. We have seen that data and renal cell, hepatocellular, and other diseases, so nothing that really stood out in my mind.

The study showed ultimately that in patients with cisplatin-eligible disease, the response rate was 30%, patients with cisplatin-ineligible disease response rate was 20%, and in patients who receive prior checkpoint inhibitors, this is a heavily pretreated population, the response rate was around 10%.

I think what's quite impressive is that patients, particularly in the cisplatin-eligible cohort, had a fairly substantial duration of response. It is going to be interesting to see how this data translates to studies that are looking at, for instance, tablets, and then with immunotherapy in the maintenance setting.

What advancements in research do you think are soon to come in the bladder carcinoma space?

I think we are quite excited at the prospect of being able to look at a combination of cabozantinib with immunotherapy as maintenance treatment for bladder cancer. There's a study that my colleague Shilpa Gupta at the Cleveland Clinic is running, looking nivolumab, which is now approved as a maintenance strategy in bladder cancer, plus or minus cabozantinib in a very timely study. Ultimately, I think that large definitive trials like that will establish the role of cabozantinib in bladder cancer.

1. Pal SK, Agarwal N, Singh P, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): Results from Cohorts 3, 4, 5 of the COSMIC-021 study. 

 40, 2022 (suppl 16; abstr 4504). doi: 10.1200/JCO.2022.40.16_suppl.4504

Articles

In the phase 1b COSMIC-021 trial, the combination of cabozantinib and atezolizumab showed clinical activity with manageable toxicity across several setting in urothelial carcinoma.

Dr. Sumanta K. Pal discusses promising immunotherapy/TKI combo in bladder cancer

Prostate cancer breaks down into four main groups, very low grade, low grade, intermediate and high grade. Many low-grade prostate cancers do not need to be treated and patients can go on active surveillance, and it doesn’t affect overall survival or quality of life. However, for cancers that need treatment, rather than turning to the tried-and-true radiation and prostatectomy routes first, as we used to, we now look for less invasive approaches that allow patients to maintain their quality of life, and especially, their continence and erectile function.

Focal therapies, like high intensity focused ultrasound (HIFU), have become the middle ground between active surveillance and more radical therapies like surgery or radiation. HIFU is for men whose cancer is localized, meaning it has not spread beyond the walls of the prostate, and whose doctors identify as good candidates. HIFU is used to burn away (ablate) the cancer without damaging the surrounding structures that control a man’s continence and erectile function.

HIFU has fewer side effects for patients than other focal therapies using energy sources including irreversible electroporation, cryotherapy, photodynamic therapy, focal laser ablation or laser interstitial thermotherapy, radiofrequency ablation, and focal brachytherapy. 

When we do the HIFU procedure, we do not make any incisions. We can perform HIFU and retreat if needed, again with HIFU, or radiation or surgery if the cancer ever returns. Multiple studies have shown HIFU’s effectiveness over the last 10 years. Men are treated in an outpatient setting, leave the hospital, typically with a catheter, and are generally back to their lives within a week.

Selecting HIFU over other innovative focal therapies for prostate cancer

There are other focal options I have explored for treating prostate cancer, including cryotherapy and brachytherapy, but the targeting of the tumors is done through cognitive fusion, and that can be difficult. 

With HIFU I can treat the tumor inside the MRI and deliver radiofrequency ablation. Another option is cryotherapy, but this often requires the patient to actually be inside the MRI machine and that can take up to 4 hours.

TULSA or Transurethral Ultrasound Ablation is a minimally invasive procedure that uses directional ultrasound to produce very high temperatures to ablate (destroy) targeted prostate tissue, similar to HIFU. However, the procedure is performed in an MRI suite and the probe goes into the urethra (versus the anus), which requires a cooling method. As most cancers are in the peripheral prostate, it makes more sense to treat transrectally, except when tumors are at the apex, then any focal therapy may have some issues reaching the tumor. 

Focal One, the most advanced HIFU technology which fuses MRI imaging and biopsy data, gives me the precise location of the tumor and allows me to create a contour around it and easily direct the HIFU energy to ablate it. The patient is going to get better results when we target the tumor in real time. For some patients, rectal access to the prostate cancer causes less symptoms like burning and dysuria.

To be very frank, while the energy source we deliver, HIFU, cryo, microwave or RFA (radiofrequency ablation) is central to tissue destruction, the technology we use to deliver it may be even more important: to deliver precise, focused treatment exactly where you want it to go, avoiding injury to the nerves, blood vessels, urethra and rectum.  

Urologists worry about any transrectal therapies, and the small risk of creating fistula tracks or other issues in the rectal wall. But the HIFU technology allows us to see where the rectal wall is by using a sensor to divert the ultrasound energy if we come too close. HIFU allows us to treat where we want and not where we don’t. I recall talking to my surgical oncology friend who uses HIFU for liver cancer because he can literally treat tissue that is next to the vena cava – the largest vein in the body -- without injury.

HIFU’s legacy is being able to treat prostate cancer with minimal side effects

HIFU’s legacy is that now we’re able to treat prostate cancer with minimal side effects to the patient because we can specifically target the lesion and not treat any other tissue, nerves or arteries, or anything that's in the vicinity of the prostate that's going to affect the patient's overall urinary function or erectile function. This makes a significant difference in the lives of the men we treat -- and their partners—or future partners. We can’t underestimate the value of preserving their quality of life as we treat their cancer.

Jennifer Linehan, MD, is a board-certified urologist and director of Urology Translational Research and an associate professor of Urology and Urologic Oncology at the Saint John’s Cancer Institute. She also practices general urology, including both male and female voiding dysfunction and treatment for kidney stones.

"HIFU allows us to treat where we want and not where we don’t," writes Jennifer Linehan, MD.

Why favor high intensity focused ultrasound for treating localized prostate cancer?

 associate professor at UT Southwestern Medical Center, discusses the FDA-approved therapy tivozanib (Fotivda) for patients with relapsed or refractory advanced renal cell carcinoma, including ongoing trials further exploring the agent.

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Tivozanib (Fotivda) is approved by the FDA for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma who have received 2 or more prior systemic therapies.

Dr. Tian Zhang discusses tivozanib for advanced kidney cancer

The number of new cancer treatment options has increased tremendously over the past 20 years, resulting in significant improvements in patient outcomes. Despite these improved therapies, most patients will eventually develop drug resistance and disease recurrence. Scientists continue to develop new drugs and drug combinations to overcome resistance, but the cycle often continues with patients developing resistance to these therapies, as well. Researchers in Center of Excellence for Evolutionary Therapy at Moffitt Cancer Center are thinking outside the box and studying an alternative approach called adaptive therapy that is based on evolutionary principles and mathematical modeling. 

In a new article in eLife, the researchers report updated results from a pilot clinical trial evaluating an adaptive therapy approach using the drug abiraterone to treat patients with metastatic castrate-resistant prostate cancer.

The Moffitt team developed their clinical trial based on a hypothesis guided by evolutionary principles; while resistance will develop in all tumors, not all resistant cells will have the ability to grow and survive because they need to compete with sensitive cells for limited resources. Therefore, the researchers’ goal was to maintain a population of drug sensitive tumor cells that could keep resistant cells in check through competition.

“Evolution-based models show current treatment strategies, which apply therapy at maximum tolerated dose until progression, are often not evolutionarily optimal,” said Robert Gatenby, MD, co-director of the Center of Excellence for Evolutionary Therapy. “While an initial response may be large, therapy fails because it strongly selects for resistance while eradicating all treatment sensitive cells. The resistant cells are now free from competition with sensitive cells, an evolutionary dynamic termed ‘competitive release,’ which allows for rapid proliferation.”

Rather than using a conventional treat until progression approach, Moffitt researchers wanted to investigate the potential benefits of an adaptive therapy approach that bases the dose and timing of a drug on a patient’s response to therapy. They conducted a pilot clinical trial in 17 patients with metastatic castrate-resistant prostate cancer. Treatment with abiraterone was discontinued when a patient’s biomarker PSA levels decreased by more than 50% of baseline levels. When a patient’s PSA levels increased again, abiraterone treatment was reinitiated, and the cycles of biomarker testing and drug withdrawal/retreatment continued. The feasibility and clinical benefit of the adaptive abiraterone therapy was reported in Nature Communications in 2017.

In this updated analysis with four additional years of follow-up, they found that patients treated with the adaptive therapy approach had a significantly longer median time to development of cancer progression (33.5 months vs. 14.3 months) and a longer overall survival (58.5 months vs. 31.3 months) than patients treated with the standard continuous treatment until progression approach. All patients treated with the standard approach developed progressive disease and died by the time of the report, but four patients on the adaptive therapy approach still have no evidence of progression and are alive. Importantly, patients treated with adaptive therapy were off treatment 46% of the time during the trial, which can reduce drug side effects and expenses. A recent economic analysis of the study found that this could reduce the average expense per patient by $70,000 per year.

The Moffitt team performed a follow-up mathematical analysis of the interactions between resistant and sensitive tumor cells and identified strategies to further improve patient outcomes. Their analysis revealed that every patient in the control group could have benefited from the adaptive therapy approach. Furthermore, they discovered that delaying the withdrawal of abiraterone resulted in the death of too many drug sensitive cells, which resulted in higher levels of resistant cells and poorer patient outcomes. This often occurred because radiographic imaging took place several months after changes in PSA levels, leading to delays in drug withdrawal. The researchers believe that addressing these trial design issues could lead to even better patient outcomes in future adaptive therapy trials in prostate cancer patients.

“These analyses illustrate the critical role for inclusion of mathematical models, evolutionary first principles and computer simulations in trial design. Unlike conventional clinical trials, this approach allows both cohort and patient-specific analyses. Furthermore, the simulations critique trial design and performance thus providing guidance for alternative strategies and future investigations,” said Jingsong Zhang, MD, PhD, principal investigator of the adaptive therapy trial and associate member of the Genitourinary Oncology Department at Moffitt.

This study was supported by the National Cancer Institute (R01CA170595, U54CA143970, P30-CA076292), the James S. McDonnell Foundation, the Jacobson Foundation and the European Union’s Horizon 2020 research and innovation program (No. 690817).

“These analyses illustrate the critical role for inclusion of mathematical models, evolutionary first principles and computer simulations in trial design. Unlike conventional clinical trials, this approach allows both cohort and patient-specific analyses," said Jingsong Zhang, MD, PhD.

Moffitt study shows adaptive therapy improves outcomes, reduces care costs for prostate cancer patients

Novartis announced in a news release that it has resumed production of 

Lu-PSMA-617 (lutetium Lu 177 vipivotide tetraxetan; Pluvicto), along with screening and enrollment for all global clinical trials of the targeted radioligand therapy.

Lu-PSMA-617 is FDA-approved for the treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

The company has also resumed production and clinical trials (US and Canada) of another of its radiopharmaceuticals, lutetium Lu 177 dotatate (Lutathera), which is FDA-approved for the treatment of patients with gastroenteropancreatic neuroendocrine tumors.

Novartis announced in May 2022 that it had taken voluntary action in temporarily suspending the clinical trials, as well as activity at its production sites in Ivrea, Italy, and Millburn, New Jersey, to address potential quality issues in the company’s production processes.

In today’s news release announcing that production had resumed at these facilities, the company noted that it “has remediated the issues that led to the temporary, voluntary suspension of production in May.”

Novartis added, “We recognize that this situation has affected—and is still affecting—patients, their families and care teams. Product quality and patient safety remain the company’s top priorities. We expect that product supply may be initially limited, and we are working hard to resume full production capacity and meet patient demand as quickly as possible. We continue to communicate with health authorities, and they are aware that we have restarted production and that the delivery of patient doses has resumed.”

Lu-PSMA-617 (also known as LuPSMA) is specifically approved by the FDA for the treatment of patients with PSMA-positive mCRPC in the post androgen receptor pathway inhibition, post taxane-based chemotherapy setting.

The approval of LuPSMA is based on findings from the phase 3 VISION trial. In the study, adding LuPSMA to standard of care (SOC) led to a nearly 40% reduction in the risk of death versus SOC alone in patients with progressive PSMA-positive mCRPC.

The findings, which were presented during the 2021 ASCO Annual Meeting, showed that at a median follow-up of 20.9 months, the addition of LuPSMA improved the median overall survival (OS) by 4 months over SOC alone (HR, 0.62). Adding the targeted radioligand therapy also led to a 5.3-month improvement in median radiographic progression-free survival (rPFS), translating to a 60% reduction in the risk of progression or death (HR, 0.40).

Along with the approval of LuPSMA, the FDA also approved a kit for the preparation of gallium Ga 68 gozetotide injection (trade name for kit, Locametz). Following radiolabeling, this imaging agent can identify PSMA-positive lesions through a PET scan.

1. Novartis resumes production and delivery of radioligand therapy medicines ahead of schedule. Published online June 30, 2022. Accessed June 30, 2022. https://bit.ly/3Oy6jYL

2. Novartis provides update on production of radioligand therapy medicines. Published online May 5, 2022. Accessed May 6, 2022. https://bit.ly/3yeMFM6

3. Novartis Pluvicto™ approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. March 23, 2022. https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant-prostate-cancer

4. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol 39, 2021 (suppl 15; abstr LBA4)

177Lu-PSMA-617 is FDA-approved for the treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer.

177Lu-PSMA-617 production, trial enrollment resumes

, discusses men’s health and fertility issues experienced by patients after having COVID-19. Sadeghi-Nejad is a professor of Surgery/Urology at Rutgers New Jersey Medical School, chief of Urology at the VA NJ Health Care System, and the director of the Center for Male Reproductive Medicine at the Hackensack University Medical Center.

“It’s important for men to be aware that there are scientific mechanisms through which COVID-19 can affect male sexual function and male reproductive function," says Hossein Sadeghi-Nejad, MD.

Dr. Sadeghi-Nejad discusses men’s health and fertility issues related to COVID-19



For patients with low-grade upper tract urothelial carcinoma (LG-UTUC), one of the most common forms of bladder cancer in the United States, recent advancements and research updates have provided additional factors for patients and providers to consider for optimizing outcomes. In this new 

The Evolving Treatment Landscape of Low-grade Upper Tract Urothelial Carcinoma

, leaders in the management of bladder and urinary tract malignancies discuss key factors affecting the diagnosis and treatment of LG-UTUC. In the first interview of the series, Jennifer A. Linehan, MD, provides an overview of the disease landscape and offers expert perspective on factors affecting recurrence and progression.

 What are the most common risk factors associated with developing low-grade UTUC?

[One of] the most common risk factors for low-grade urothelial carcinoma [is] a history of bladder cancer, either low- or high-grade. Patients [who] have known Lynch syndrome have a risk of low-grade UTUC. Patients who are smokers, have a history of smoking, or [have other] risk factors such as exposure to aniline dyes [or] aristolochic acid exposure over time [are at-risk]. Patients who may be working with certain chemicals such as chemicals you would stain wood with or paints or those types of exposures [are also at-risk].

The incidence of low-grade UTUC is about 30%. So 5% to 10% of all of the urothelial carcinomas are of the upper tract, and of that 5% to 10%, 30% are low-grade. This number is increasing, and I think it's more because our imaging and our way of monitoring patients has improved. It's hard to say if that's the actual incidence or if we're just finding more low-grade epithelial UTUCs.

 What characteristics distinguish low-grade disease from high-grade disease?

There are imaging characteristics as well as some pathologic markers that will distinguish low-grade from high-grade disease. When you're examining patients and have them undergoing imaging, you may be looking in the bladder, up in the kidney, [or] up in the ureter. Any patients [who] have very large tumors, especially tumors greater than 2 cm; patients [who] have characteristics of the tumor invading the kidney or surrounding tissues on imaging; patients [who] have lymphadenopathy and large lymph nodes—even though it's within the pelvis near the bladder—[all have] signs to me that this could be a high-grade versus a low-grade cancer. From a molecular perspective, patients [who] have higher-grade disease have a higher predisposition [to] the 

 mutation. In fact, we think that 60% to 75% of patients with UTUC have the 

 What are the typical signs and symptoms of low-grade UTUC when a patient presents to your clinic? What tests or procedures are involved in diagnosing low-grade UTUC?

Most of my patients with low-grade UTUC have presented with hydronephrosis on imaging and microscopic hematuria. Occasionally, I will also see gross, painless hematuria. Some patients will just come in with flank pain, and obviously, there'll be abnormalities on imaging that will lead me into that diagnosis. Then, of course, we perform ureteroscopy and find if it's low-grade or high-grade.

In my practice in diagnosing low-grade UTUC, I usually get imaging with the CT (computed tomography) urogram. You can also do MR (magnetic resonance) urogram, which I've been doing more in the era of contrast shortage. I think the only thing you're losing there is [that] you may not be able to see some stones. Either a CT urogram or an MR urogram—I think both are equally good, depending on your institution. I do urine cytology in the clinic; [however], for upper tract disease, especially if it's low-grade, the value of finding something is probably minimal. I think urinalysis is always important. You want to see how much microscopic hematuria is there. Then, of course, [for] any patients [who] can't have contrast for whatever reason, [such as] renal function or contrast allergy, I think retrograde pyelogram is always a good test to see if there's a filling defect within the collecting system.

If a patient is confirmed to have low-grade disease, what are the most concerning complications that can result if they don't receive effective and timely treatment?

When I'm treating a patient with low-grade UTUC, there are a couple of concerning factors for me that I want to make the patient aware [of in order to] have a good discussion about [them]. First, I think every urologist is always worried about missing some high-grade urothelial carcinoma in the tumor as well. I think making the diagnosis is most important. I always tell my patients that they have to understand that—even when there is no high-grade disease, even with low-grade UTUC—the risk of recurrence is high. There are some studies that report up to as high as a 76% recurrence rate for low-grade UTUC. [It is important to] understand that the recurrence rate is high; that while these cancers may not be dangerous in the setting of metastasis, they can harbor higher-grade cancers that we may not have found yet; and that the work-up is probably the most important combining pathology with biopsies as well as cytology when I'm doing ureteroscopy.

The cancer [may be] undertreated, for example, if I have a tumor that's in the lower pole of the kidney, and for some reason, I just can't get the scope around the bend into the lower pole. [If] I feel like I [couldn’t] laser it completely, [or if] I feel like I wasn't able to extract the tumor with a basket and then cauterize the tumor where I'm clearly aware that I may be leaving some disease behind, tumors in these patients are 100% going to recur. The tumor can grow, and if left untreated, that can flourish into high-grade disease.

How concerning is progression from low-grade UTUC to high-grade disease?

Concerning recurrence as well as progression of low-grade UTUC, recurrence is clearly my biggest concern. In patients, [I] make sure that I've adequately treated the tumors that are there. I know these patients [who have tumors with] a high likelihood [of recurring], so I'm going to monitor them closely, perhaps even do ureteroscopy every 3 months to make sure I've treated the tumor if I'm not using surgery plus some adjuvant treatment. As far as progression, I base that on the size. If I see very large tumors up in the collecting system, even if my biopsies are negative, if the tumors are greater than 2 cm, [such as] 3 or 4 cm, I'm always concerned that these could be harboring some high-grade disease. While that's not exactly considered progression, I think that's always some concern. For patients [who] have smaller tumors that are sitting in the ureter or sitting in the collecting system, especially if they're under 1 cm, there's a very low risk of progression to high-grade disease.

 What disease characteristics do you use to classify tumors as resectable or nonresectable?

When I classify tumors of the upper tract as resectable versus nonresectable, I think of that in 2 settings. I think of the patients who have low-grade disease who have larger tumors or tumors in areas of the kidney or the ureter that I can't completely resect. Then I also think of patients with high-grade disease where the tumors may be extensively outside the kidney, invading other organs and even perhaps have some lymph node involvement. In this setting, if we're talking specifically about low-grade [disease], those are tumors that are in the area of the kidney where I just may not be able to get my flexible ureteroscope, where I may not be able to laser, where I may not be sure that I've taken care of everything. [The] tumors may [also] be [too] large. [If] I go in, do ureteroscopy, start to remove the tumor [with the] laser, and all of a sudden, it's getting really bloody, [and] I can't see anymore, [then] I have to come back another day. If I come back to treat a tumor 1, 2, [or] 3 times, those are the patients [for whom] I'm really worried that I'm dealing with more unresectable disease.

In this companion article, Jennifer A. Linehan, MD, from the John Wayne Cancer Institute in Santa Monica, California, shares expert insight into factors affecting LG-UTUC diagnosis and treatment. 

EP. 1B: Low-grade Upper Tract Urothelial Carcinoma: Disease Overview

A newly discovered inhibitor of a common cancer-causing protein operates selectively, reducing expression of genes that fuel rampant cell proliferation and alter the epigenome, according to a Northwestern Medicine study 

The protein, called MYC, was previously considered “undruggable,” but these new findings demonstrate that certain inhibitors may selectively affect pro-cancer processes, according to Debabrata Chakravarti, PhD, the Anna Lapham Professor of Obstetrics and Gynecology, vice chair for translational research in the Department of Obstetrics and Gynecology and co-senior author of the study.

“These findings create the foundation to build and test all new lines of compounds for MYC inhibition,” said Chakravarti, who is also a professor of Pharmacology and assistant director of shared resources at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

MYC is a transcription factor protein that generally upregulates genes involved in cell proliferation. The transcription factor is persistently hyper-expressed in many cancers, but designing inhibitors is complicated by both the protein’s unusual structure and its considerable influence beyond cell proliferation, meaning previous inhibitors had serious toxic side-effects.

In the current study, investigators administered a small-molecule inhibitor called MYCi975 to prostate cancer cells, examining the effects on gene expression throughout the human genome. Rather than broad downregulation of all MYC targets, unexpectedly, the MYCi inhibitor had variable effects — upregulating some genes, downregulating others and sparing some altogether.

“This is how we could glean information about selectivity of the drug,” said Austin Holmes, a recent graduate of the Driskill Graduate Program in Life Sciences (DGP) and the lead author of the study.

Importantly, some genes which are essential for cellular functionality — and that may have been responsible for toxicity in previous MYC inhibitors — were untouched, according to Sarki Abdulkadir, MD, PhD, the John T. Grayhack, MD, Professor of Urological Research, vice chair for research in the Department of Urology and co-senior author of the study.

“Not all MYC functions were abrogated,” said Abdulkadir, who is also a professor of Pathology and a principal investigator of the Specialized Program of Research Excellence (SPORE) in prostate cancer at the Lurie Cancer Center. “This gives us some selectivity that has not been shown before.”

On the other hand, several cancer-associated targets of MYC were downregulated, preserving the inhibitor’s anti-cancer effects. The realization that MYC inhibitors can exert a variable effect on downstream gene targets of MYC provides a new path forward for drug development, according to Chakravarti.

“Excitingly, in animal models, MYCi975 enhances the efficacy of enzalutamide anti-hormone therapy. Our hope is to use this platform to analyze the second or third generation of compounds, and to explore how these drugs may interact with established anti-cancer therapies,” Chakravarti said. “This study is also a prototype of how collaborative research can lead to significant discoveries in biomedical research.”

Co-authors of the study include James Parker, PhD, research assistant professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine; Vinay Sagar, PhD, postdoctoral fellow; Mihai Truica, student in the Medical Scientist Training Program (MSTP); Pritin Soni, research technologist; Huiying Han, former senior research associate; and Gary Schlitz, PhD, research professor of Pharmacology.

This work was supported by grants from the National Cancer Institute (R01CA196270, R01CA257258, P50CA180995, F30CA250196 and T32GM008061) and a Prostate Cancer Foundation Challenge Award. Part of this work was supported by the Polsky Urologic Cancer Institute and NUSeq Core Facility of Northwestern University.

In a recent study, investigators administered a small-molecule inhibitor called MYCi975 to prostate cancer cells, examining the effects on gene expression throughout the human genome.

Genome-wide intricacies of cancer inhibitor untangled

, director of the Kidney Cancer Program at Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, lists several areas of unmet need in the treatment paradigm for patients with renal cell carcinoma.

Understanding the mechanisms of treatment resistance is among the areas of unmet need, says James Brugarolas, MD, PhD.

Dr. Brugarolas on unmet needs in the renal cell carcinoma treatment paradigm

Physicians with lower self-rated health and life satisfaction, and those who experienced a recent serious injury or illness, are more likely to be sued by patients for medical negligence, according to a new study.

Researchers analyzed data from 12,134 doctors in Australia and found psychosocial and workplace factors associated with risks of being sued. Those are in addition to risks of lawsuit against older surgeons with high workloads, long work hours and history of prior claims, said the study, published this month in the 

“This suggests that the quality of treatment and workplace support offered to doctors experiencing recent illness or injury can impact on patient care,” the authors wrote. “Our results also reinforce pervious recommendations that preventive efforts to improve doctors’ health and well-being need to be intensified.”

“It is critical that we try to better understand why some doctors are sued. A mistake by a doctor can have tragic consequences for patients and can be costly for the health system,” corresponding author Owen Bradfield, a fellow of the Royal Australian College of General Practitioners, said in a news release.

“Patients who suffer harm from a medical error can sue the doctor concerned in order to seek redress, answers, and assurances that mistakes will not be repeated,” said Bradfield, medical lawyer and doctoral candidate at the Centre for Health Policy, Melbourne School of Population and Global Health at the University of Melbourne. “Therefore, understanding why that doctor made a mistake and was sued can help us reduce medical errors and improve healthcare quality.”

The study examined responses of physicians in the Medicine in Australia Balancing Employment and Life (MABEL) survey. Doctors answered questions about their age, sex, specialty, personality, health, life satisfaction, working conditions and previous lawsuits.

Among the group, 649 reported being named in a medical negligence claim, including 268 general practitioners.

Based on sex, working in a regional area, low self-rated life satisfaction and not achieving work-life balance, along with increasing age, predicted negligence claims for male doctors. Working more than part-time hours and having recent personal injuries or illnesses predicted claims for female doctors.

“Personality type predicted claims in both male and female doctors,” the study said. The researchers “found that agreeableness, unlike other personality types, conferred a modest protective effect on the risk of being sued.”

While prior studies have not found a consistent association between personality type and risk of lawsuit, agreeableness is associated with empathy, which may improve professionalism and communication. “Personality may influence how a doctor responds following and adverse event, and this may also determine the risk of medical litigation,” with patients possibly less angry and less likely to sue doctors who express genuine empathy and regret, the authors wrote.

The researchers advised cautious interpretations for associations of work hours and perceptions about job control, with medicolegal risk. For example, greater risk due to physician work hours could be explained by increased patient volume, while doctors in highly structured workplaces may feel they have less autonomy, but may have well-defined scopes of practice, surgical safety checklists or patient safety initiatives that reduce medical errors.

The study noted a relative undersupply of physicians in regional and remote areas of Australia, with similar problems in the United States and Canada. Physicians in regional settings had greater risk of lawsuit than those in remote areas – a surprising finding because generally they expected risk to increase with geographic remoteness. Explanations could include increased amounts of procedural work at small hospitals and less familiarity with patients that leads to errors from lack of continuity of care.

1. Bradfield OM, Bismark M, Scott A, Spittal M. Vocational and psychosocial predictors of medical negligence claims among Australian doctors: a prospective cohort analysis of the MABEL survey. 

“Our results also reinforce pervious recommendations that preventive efforts to improve doctors’ health and well-being need to be intensified,” the authors wrote.

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Study assesses physician workplace and psychosocial factors as predictors of medical negligence claims