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Children’s Cancer Institute
A drug that previously fell short of expectations holds promise for treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The drug, PR-104, was originally designed to target hypoxic cells in solid tumors, but it showed less activity than expected in clinical trials, and its development was suspended.
Now, preclinical research has shown that PR-104 can be activated by AKR1C3, an enzyme that is overexpressed in T-ALL.
The researchers described this work in Blood.
“We were so encouraged by our first results with PR-104 that we undertook additional studies which showed the drug to be preferentially active against T-ALL . . . ,” said study author Richard B. Lock, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia.
“We believe that PR-104 might be an effective drug for patients who have initially benefited from conventional treatment for T-ALL but who have subsequently relapsed.”
Developing PR-104: A rocky road
PR-104 is a phosphate ester of the nitrogen mustard prodrug PR-104A. It was invented by William R. Wilson, PhD, of the University of Auckland (UoA) in New Zealand, and licensed to a UoA start-up company called Proacta Inc.
In a phase 1 study of patients with solid tumor malignancies, PR-104 failed to produce responses. The drug did elicit responses in a phase 1/2 trial of patients with advanced ALL or acute myeloid leukemia, but results fell short of expectations, and Proacta suspended development of PR-104.
Another drug Proacta was developing, PR-610, also failed to meet expectations. Because of these setbacks, the company closed its doors.
“As a fragile start-up, [Proacta] could not survive two serial ‘failures’ in phase 1/2,” Dr Wilson said. “Arguably . . . , the failure was more to do with the attempt to develop these compounds without biomarker support . . . than lack of potential of the compounds. Interestingly, PR-610 has subsequently been licensed by UoA to Threshold Pharmaceuticals, who are continuing its development (with biomarker support) as TH-4000.”
“We have a more challenging problem with PR-104 because the original patents have lapsed thanks to the decision of the UoA to not maintain the national phase filings after Proacta pulled the plug. [However,] as a result of [Dr Lock’s] work, it is now clear that PR-104 has exciting potential in leukemias with high activity of
AKR1C3.”
Results in T-ALL
Dr Lock and his colleagues tested PR-104 in a panel of 7 patient-derived pediatric ALL xenografts. Two weekly doses of PR-104 at 200 mg/kg significantly delayed progression in both T-ALL (n=4) and B-cell-precursor (BCP) ALL (n=3) xenografts.
The delay ranged from 10.3 days to 59.2 days and was significantly longer for the T-ALL xenografts (P=0.03).
PR-104 produced objective responses in all 4 T-ALL xenografts, including 2 complete responses. The drug also produced complete responses in 2 of the 3 BCP-ALL xenografts, but the third exhibited progressive disease.
Additional experiments showed that AKR1C3 expression was significantly higher in T-ALL than BCP-ALL, and AKR1C3 was “a major determinant” of sensitivity to PR-104, both in vitro and in vivo.
The researchers confirmed this by overexpressing AKR1C3 in a resistant BCP-ALL xenograft. Once AKR1C3 was overexpressed, the team observed “dramatic sensitization” to PR-104.
The path ahead
Now, Dr Lock and his colleagues are trying to determine why T-ALL cells express high levels of AKR1C3.
“If we can work out what activates this enzyme in T cells, we might find a way of activating it in B cells, making the B-cell disease sensitive to the drug as well,” Dr Lock said. “Obviously, it would be ideal if we could extend this drug’s reach to include all acute lymphoblastic leukemia patients.”
“In the meantime, we can envisage using PR-104 to target highly aggressive T-ALLs that express high levels of AKR1C3. We are in the process of working with our clinician colleagues in Australia and the US to organize a clinical trial of PR-104 in T-ALL.”
Dr Wilson noted that finding a path forward for PR-104 will be challenging due to the lack of patent support.
“[But] there are two reasons that make me think it is worth trying to do so,” he said. “One is the proximate concern that there are kids with high-AKR1C3 leukemias (adults too) who could benefit from this opportunity. The other is that this problem links to a looming paradigm shift in drug development. As we dissect cancer based on molecular analysis . . . , the commercial model will have to change.”
“There will still be ‘blockbuster’ drugs from time to time that address very high numbers of cancers . . . , but my expectation is that most cancer control in the future will depend on understanding the peculiarities of individual tumors and matching these with drugs that exploit these features. PR-104 is currently stuck in the past but could be a poster child for that future.”
