Drug Repurposing for CD

Drug repurposing for Castleman Disease

Though only one treatment is FDA approved for one subtype of Castleman disease, several treatment approaches are well established for the various subtypes of Castleman disease. Approximately 90% of UCD patients are successfully treated with surgical excision and approximately 90% of HHV8-positive MCD are successfully treated with rituximab/Rituxan, which is not approved for HHV8-positive MCD but is a great example of effective drug repurposing. About one-third to one-half of iMCD patients are successfully treated with siltuximab/Sylvant, which is FDA-approved for iMCD. For the remaining UCD, HHV8-positive MCD, and iMCD patients that do not benefit from these therapies, several drugs have been identified as potential repurposed treatments and extensive research is underway to uncover more.

The CDCN’s drug repurposing approach has led to the successful identification of drug targets and drugs that can help CD patients. The CDCN’s co-founder and executive director, Dr. David Fajgenbaum, also a patient with iMCD, began testing one of these drugs on himself in 2014 and is currently in his longest remission ever (read more about his “Chasing My Cure” story here). See below for details about the CDCN’s successful drug repurposing efforts.

The drug Dr. David Fajgenbaum discovered as a potential repurposed treatment and tested on himself is called sirolimus/Rapamune. It was FDA-approved for organ transplant rejection in 1999 and repurposed and subsequently FDA-approved for the treatment of the rare disease lymphangioleiomyomatosis (LAM) in 2015. Sirolimus works by inhibiting the mTOR signaling pathway. Signaling pathways are communication lines that cells use to exert functions and communicate with one another. Dr. Fajgenbaum discovered its potential for treating CD in 2014 after multiple relapses with iMCD and failure to respond to siltuximab (the only FDA approved drug for iMCD). This brings up an important point – drug repurposing can be done several times and even in parallel with other diseases to maximize a drug’s utilization to its full potential. 

Knowing that his only chance for survival would be to identify an existing treatment that could be repurposed for iMCD, Dr. Fajgenbaum pursued several paths to discover and test a repurposed treatment:

• Literature analysis was performed to identify FDA-approved drugs that had been tried for iMCD patients; Dr. Fajgenbaum found cyclosporine had been tried as a repurposed drug for iMCD in Japan and tested it on himself, but it did not work for him 
• Published literature for related diseases was also reviewed; IVIg was found to be promising for several diseases similar to iMCD, so Dr. Fajgenbaum tried IVIg on himself which seemed to have a modest effect but additional treatments were clearly needed
• In-depth experimentation on lymph node tissues and blood samples, including cytokine quantification, flow cytometry, serum proteomics, and immunohistochemistry to identify defects in Dr. Fajgenbaum’s samples; he identified the mTOR signaling pathway as being highly activated and a potential drug target 
• Dr. Fajgenbaum searched for FDA approved drugs known to inhibit the defect he found in his own samples (mTOR hyperactivation) and began testing the mTOR inhibitor sirolimus on himself; he has been in an extended remission for over seven years. This was reported in the New York Times and published in the Journal of Clinical Investigation.
• The CSTL has performed further studies to confirm mTOR is highly active in many other patients.
• The ACCELERATE natural history registry was used to capture data on other patients with iMCD and UCD that were treated with sirolimus.
• After several other Castleman disease patients demonstrated a response from sirolimus, a clinical trial was launched to systematically assess its effectiveness.

As a result of the work of the CDCN and Dr. Fajgenbaum,  sirolimus has also been given to numerous patients with iMCD and UCD. Essentially, this process involved pulling together various datasets, from prior work in both CD and related diseases, and new data from patient samples from various institutions to identify a new therapeutic drug target (mTOR) and an existing drug known to inhibit mTOR that can be used in a new way.

If you would like more information about the clinical trial, please contact CDTrial@pennmedicine.upenn.edu. If you want to join ACCELERATE so that your medical records and samples can be used for research, please contact Bridget bridget.austin@pennmedicine.upenn.edu.

For more about this approach, check out the video below and these links:

• Chasing My Cure
• Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade–refractory idiopathic multicentric Castleman disease
• Increased mTOR activation in idiopathic multicentric Castleman disease

Sirolimus is not the only success story of CDCN’s drug repurposing. A more recent example is the identification of the JAK-STAT pathway’s importance in CD and repurposing of an existing drug. 

This was done through a three-tier approach:

1. A large serum proteomics study and pathway analysis
2. A laboratory (in vitro) study to confirm the findings
3. Matching the defects found in the laboratory to an existing drug that is already used for a disease that is similar to CD

The CDCN conducted a large serum proteomics study that measured 1,300 proteins in almost 100 CD patient samples. Notably, this study was able to help develop a 7-protein test that can help to identify patients most likely to benefit from siltuximab or not. Additional analyses on this proteomics data helped identify that the JAK-STAT pathway seems to be highly active in iMCD patients and inhibiting it may be helpful for stopping the disease. 

Then, one of the former members of the CSTL team, Dr. Ruth-Anne Langan Pai, a recent graduate of UPenn’s Immunology PhD program, performed single cell RNA sequencing and in vitro studies that confirmed in the lab that inhibiting JAK with a drug called ruxolinitib could potentially be helpful for iMCD. 

In parallel, the team found that ruxolitinib, which is approved for a disease similar to iMCD called myelofibrosis, was being used off-label for another similar disease called Hemophagocytic lymphohistiocytosis (HLH). Given these findings, Dr. Fajgenbaum suggested that ruxolinitib could be considered for two iMCD patients that were out of treatment options. Both patients improved with the initiation of therapy and further research is underway to study ruxolitinib as a treatment for CD patients who do not respond to siltuximab or sirolimus. 

Check out the following links about this work:

• Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease
• Adrenalitis and anasarca in idiopathic multicentric Castleman’s disease

More research is underway to identify repurposed treatments for all forms of Castleman disease. In fact, one of the primary goals of the studies in the CDCN’s Research Pipeline is to discover additional treatment targets that can be addressed with repurposed drugs.