HemOnc Today's PharmAnalysis
HemOnc Today's PharmAnalysis
April 15, 2019
4 min read

Trial to assess novel targeted therapy for rare form of kidney cancer

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Photo of Pavlos Msaouel
Pavlos Msaouel

A preclinical study that yielded new insights into a rare pediatric malignancy laid the foundation for a phase 2 trial that is evaluating a novel treatment approach in a specific type of kidney cancer.

Investigators at The University of Texas MD Anderson Cancer Center developed a mouse model of malignant rhabdoid tumors, an aggressive childhood malignancy that is caused by mutations in the SMARCB1 gene and often starts in the kidneys.

Researchers determined that blocking proteasome degradation and autophagy — two mechanisms important for clearing protein waste — led to complete regression of these tumors, for which there are no effective targeted treatments.

Based on those findings, the researchers developed a trial to evaluate the combination of chemotherapy and a proteasome inhibitor for treatment of adolescents and young adults with renal medullary carcinoma, a rare malignancy also characterized by SMARCB1 mutations. Adolescent and adult patients who developed malignant rhabdoid tumors in their kidneys also will be eligible to enroll.

“This is the first trial designed specifically for SMARCB1-mutant renal medullary carcinoma,” Giannicola Genovese, MD, assistant professor of genitourinary medical oncology at MD Anderson, said in a press release. “There is a need for new therapies for treating these patients. I think we’ve developed a good platform for discovery, to provide options for these patients and hope for the families, as well.”

HemOnc Today spoke with Pavlos Msaouel, MD, PhD, assistant professor in the department of genitourinary medical oncology at MD Anderson, about the insights gleaned from the preclinical study, how they led to the development of the phase 2 trial, what the investigators hope to observe and the potential implications of the findings.


Question: What prompted the preclinical study?

Answer: The lack of the SMARCB1 gene — otherwise known as INI1 — is a driver of very aggressive cancers. This deficiency often spurs kidney cancers, such as renal medullary carcinoma and malignant rhabdoid tumors. Cancers that result from the loss of this gene often occur in the kidneys, but they can also arise in other tissues. Malignant rhabdoid tumors typically occur in children aged younger than 3 years, and they are lethal. We do not have effective, approved targeted therapies. The cancer we are mainly looking at in the clinical trial is renal medullary carcinoma, which also arises from the kidneys. It is extremely aggressive and is driven by the inactivation of the SMARCB1 genes. In order to understand the biology of what the loss of this gene does to cells that makes them so aggressive, we needed pre-clinical models that would help us understand how best to target the unique biology that these cells harbor.



Q: How did you conduct that study?

A: We developed animal models that harbored cells that had inactive SMARCB1. With this tumor suppressor inactivated, we developed tumors that were similar to malignant rhabdoid tumors in the genetically modified animal model. We were able to show that the genetically modified animal models recapitulated the malignant rhabdoid tumors. We then identified pathways that may make cells vulnerable to certain targeted agents, such as proteasome inhibitors. Another crucial process identified through these models was the autophagy machinery, which can be targeted using autophagy inhibitors. Human xenografts — both from malignant rhabdoid tumors and from renal medullary carcinoma — were then transplanted into mice. We treated these mice with proteasome inhibitors and/or autophagy inhibitors, and found these treatments to be very effective.


Q: Why is the loss of SMARCB1 cells so significant?

A: SMARCB1 loss is the major driver of rare but very aggressive cancers. These include malignant rhabdoid tumors and renal medullary carcinoma, an aggressive form of kidney cancer that occurs predominantly in young African-Americans — typically in their early to mid-20s — who harbor the sickle cell trait. We need to understand how the loss of SMARCB1 drives these cancers, what makes them so aggressive, and how to best to develop clinically relevant and rational targeted therapies for these diseases. There is clearly an unmet need, which is why we are so excited about these results.


Q: Did the findings surprise you?

A: In some ways, yes, because we were still understanding the biology of these malignancies. Often you have hypotheses or preconceptions, but the data may take you to somewhat divergent avenues.


Q: Can you provide an overview of the phase 2 trial?

A: The clinical trial includes individuals who are aged 12 years or older with SMARCB1-deficient kidney malignancies. More than 90% of these patients have renal medullary carcinoma, either with or without sickle cell trait or sickle cell disease. Patients with malignant rhabdoid tumors typically are aged younger than 3 years and are not eligible for the trial due to the age restriction. There are, however, rare cases of adults with this malignancy, and they are eligible. We opened the trial in August 2018. As of late February, we had enrolled eight of the projected 30 patients. That is fast accrual for such a rare malignancy, and it shows how this is such a huge unmet need. Based on current enrollment, I wouldn’t be surprised if the trial concludes about 2 years from now.



Q: What do you expect the results to show?

A: The trial adds the proteasome inhibitor ixazomib (Ninlaro, Takeda/Millennium) to a chemotherapy regimen, which on its own produces responses and makes those cancers shrink in approximately 29% of cases. These responses are often not durable, with about 14% of patients experiencing tumor shrinkage that persists for 28 weeks or longer. Our hope is that, by adding ixazomib to the chemotherapy backbone, we will see more responses that are also durable. We want to improve the response rate from 29% to at least 50%, and we want to increase the 28-week disease control rate from 14% to at least 30%. If we do that, we are going to increase survival for these patients. Even with our best available treatments, median survival for patients with renal medullary carcinoma is only 13 months, and fewer than 5% of patients survive longer than 36 months. If we are able to produce responses in half of the patients and those responses are durable, that will make a big difference. We don’t expect that any trial will be the cure for all patients or that a regimen will be universally effective, so we also hope to understand who is resistant to these regimens and why. – by Joe Gramigna



Carugo A, et al. Cancer Cell. 2018;doi:10.1016/j.ccell.2019.01.006.


For more information:

Pavlos Msaouel, MD, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: pmsaouel@mdanderson.org


Disclosure: Msaouel reports no relevant financial disclosures.