Extraordinary therapeutic effect of PSMA radioligand therapy in treatment-refractory progressive metastatic prostate cancer with the transketolase inhibitor benfo-oxythiamine as a radiosensitizer—A case report

Extraordinary therapeutic effect of PSMA radioligand therapy in treatment-refractory progressive metastatic prostate cancer with the transketolase inhibitor benfo-oxythiamine as a radiosensitizer—A case report

• October 2024Frontiers in Medicine 11
• DOI: 10.3389/fmed.2024.1462234
• Carsten S Kramer,  Jingjing Zhang,  Richard P. Baum

Authors

Authors and Affiliations:

1. Carsten S. Kramer
- CURANOSTICUM Wiesbaden-Frankfurt, Germany
- Center for Advanced Radiomolecular Precision Oncology

2. Jingjing Zhang
- Department of Diagnostic Radiology
- Clinical Imaging Research Centre
- National University of Singapore

3. Richard P. Baum (corresponding author)
- CURANOSTICUM Wiesbaden-Frankfurt
- Center for Advanced Radiomolecular Precision Oncology
- Email: baumrp@gmail.com
- Noted as a shareholder of Benfovir AG and Oxy5 OncoMedical AG (disclosed conflict of interest)

Institutional Context:

The primary work was conducted at CURANOSTICUM Wiesbaden-Frankfurt, which is a center specializing in advanced radiomolecular precision oncology.

Prior Related Work:

The paper references several earlier studies by Baum and colleagues on PSMA-targeted therapy, including:
- 2016 work on Lu-177-PSMA radioligand therapy safety and efficacy
- Bad Berka experience with PSMA-based radioligand therapy since 2013

The paper also acknowledges Dr. Johannes Coy for "valuable discussions about transketolases," suggesting collaborative input on the mechanistic aspects of the treatment.

This was published in Frontiers in Medicine as a case report, with the following review process:
- Edited by: Madhavi Tripathi (All India Institute of Medical Sciences)
- Reviewed by:
  * Bruno Oliveira (Institute of Molecular Medicine, Portugal)
  * Carmelo Caldarella (Fondazione Policlinico Universitario A. Gemelli IRCCS, Italy)

Abstract

Herein we report, for the first time, the therapeutic response of a prostate cancer patient with the thiamine antagonist benfo-oxythiamine (B-OT) added to prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT). The patient was initially diagnosed as pT3b pN0 (0/7) M0 L0 V0 R0 G3, Gleason score 5 + 5 = 10, with an initial prostate-specific antigen (PSA) level of 4.05 ng/ml. Shortly after radical prostatectomy, ⁶⁸Ga-PSMA positron emission tomography/computed tomography (PET/CT) revealed PSMA-positive lymph node metastases. Despite treatment with androgen deprivation therapy, external beam radiation therapy, palliative chemotherapy, and five cycles of PRLT (¹⁷⁷Lu-PRLT or TANDEM-PRLT, respectively), the patient experienced progression in PSA levels as well as in PSMA PET/CT. 

Due to the intense PSMA expression, ¹⁷⁷Lu-PRLT with ¹⁷⁷Lu-PSMA-I&T was resumed for another 4 cycles (cycles 6th to 9th) and the patient was additionally treated with the thiamine antagonist benfo-oxythiamine. It was hypothesized that B-OT acts as a radiosensitizer by interfering with the repair of damaged DNA. B-OT-PRLT was well-tolerated and no substantial changes in laboratory results were observed. Additionally, the patient reported significant improvement in clinical symptoms. 

Post-treatment ¹⁷⁷Lu-PSMA single-photon computed tomography (SPECT)/CT after the 7th cycle (and after 2 cycles of B-OT-PRLT) revealed regression of metastases compared to the post-treatment SPECT/CT after the 6th cycle. Before the 8th cycle, PSMA PET/CT showed a mixed response following prior uncontrollable cancer progression. Moreover, the PSA level showed a significant decline after one cycle of B-OT-PRLT. 

Although the patient had experienced massive progression before the first cycle of B-OT-PRLT, he survived for an additional 12 months. This case supports the hypothesis that B-OT-PRLT could overcome radiation resistance in prostate cancer patients who do not initially respond to ¹⁷⁷Lu- or ²²⁵Ac-PRLT.

Summary

Here is a clear summary of this important case report from October 2024. This paper describes the first reported case of using benfo-oxythiamine (B-OT) as a radiosensitizer alongside PSMA-targeted radioligand therapy (PRLT) for treating prostate cancer. Here are the key points:

Patient Background:
- 79-year-old man with aggressive prostate cancer (Gleason score 10)
- Disease progressed despite multiple standard treatments including surgery, radiation, hormone therapy, and chemotherapy
- Previously received 5 cycles of radioligand therapy but still showed disease progression

Novel Treatment Approach:
- Combined PRLT with B-OT (a thiamine antagonist that acts as a radiosensitizer)
- B-OT works by inhibiting transketolase enzymes, which are important for DNA repair
- Treatment consisted of 4 cycles of Lu-177-PSMA therapy with B-OT (3mg/day for 2-5 days)

Results:
- Patient showed significant improvement after treatment:
  - 50% decrease in PSA levels after first cycle
  - Imaging showed regression of metastases
  - Reported improved clinical symptoms
- Treatment was well-tolerated with no significant side effects from B-OT
- Patient survived an additional 12 months despite having previously resistant disease

Significance:
This case suggests that B-OT could help overcome radiation resistance in prostate cancer patients who don't initially respond to standard radioligand therapy. A phase 1b/2 clinical trial is planned to further evaluate this combination therapy.

Important Context:
Since my knowledge cutoff is April 2024 and this paper is from October 2024, while I can summarize its contents, I cannot independently verify its findings or compare them to other potential developments in the field from after April 2024.

Prior Treatment

Let me break down the patient's condition and treatment history before the B-OT/PSMA trial:

Initial Diagnosis & Early Treatment (2014-2015):
- Diagnosed with aggressive prostate cancer (Gleason score 5+5=10)
- Had robot-assisted radical prostatectomy with lymphadenectomy
- Within 3 months, showed biochemical recurrence
- Received hormone therapy (leuprorelin) and external beam radiation

Disease Progression & Standard Treatments:
1. First Line (2017):
- Developed multiple retroperitoneal lymph node metastases
- Received 6 cycles of docetaxel chemotherapy
- Initially achieved stable disease with PSA nadir of 0.62 ng/ml

2. Second Line (2018-2019):
- Started enzalutamide
- Despite treatment, developed:
  - Local recurrence
  - Extensive lymph node metastases
  - Single bone lesion
  - PSA increased to 63 ng/ml

Evidence of Radiation Resistance:
1. Initial PRLT Treatment (2019):
- Received 2 cycles of Lu-177-PRLT (total 14.8 GBq)
- Initially achieved stable disease
- Received 2 more cycles (additional 14.2 GBq)
- Despite treatment, showed disease progression with:
  - Extensive PSMA-avid lymph node metastases
  - Bone metastases
  - Increased glycolytic activity in lymph nodes

2. Escalation to TANDEM-PRLT:
- Received combination therapy of Lu-177 (6.2 GBq) plus Ac-225 (2.1 MBq)
- Showed rapid progression despite this aggressive approach
- PSA rose to 70 ng/ml

3. Final State Before B-OT Trial (May 2020):
- Extensive disease with:
  - Multiple lymph node metastases (inguinal, iliac, retroperitoneal, mediastinal)
  - Mesenteric and peritoneal involvement
  - Bladder wall infiltration
  - Bone metastases
  - PSA level of 264 ng/ml
- Failed response to resumed docetaxel chemotherapy

The radiation resistance was established through:
1. Progressive disease despite multiple cycles of standard PRLT
2. Continued progression even after escalation to more aggressive TANDEM therapy
3. Maintained high PSMA expression (visible on imaging) despite lack of response to radiation therapy
4. Rising PSA levels throughout radiation treatments

This extensive treatment history and documented progression through multiple forms of radioligand therapy provided clear evidence of radiation resistance before the B-OT trial began.

Patient End State

The patient's final state can be described through several key aspects:

Survival Outcome:
- Survived 12 months after starting B-OT-PRLT
- Deceased in May 2021

Final Medical Conditions:
1. Renal Issues:
- Chronic renal failure (AKIN III stage)
- Required dialysis
- Macrohematuria
- Multiple renal cysts

2. Blood/Hematological:
- Anemia (Grade 2)
- Required multiple blood transfusions
- Thrombocytopenia (Grade 1)

3. Cardiovascular:
- Exertional dyspnea (NYHA II-III)
- Complete right bundle branch block
- Mild diastolic left ventricle dysfunction
- Arterial hypertension

4. Physical Decline:
- Weight loss of 10kg in 4 months (final weight 76kg at height 180cm)
- Reduced appetite
- Notably, did not experience xerostomia (dry mouth) despite extensive radiation therapy

Disease Status Near End:
- Before final (9th) cycle of treatment in January 2021:
  - PET/CT showed progression of bone and lymphatic metastases
  - PSA peaked at 315 ng/ml
  - Had urinary obstruction due to dislocated nephrostomy
  - Severely elevated creatinine (9.2 ng/ml)
  - Hyperkalemia (6.0 mmol/l)
  - Hyperuricemia (10.2 mmol/dl)

The patient's death appears to have resulted from a combination of disease progression and multiple organ complications, though the paper doesn't explicitly state the immediate cause of death.

Background of the study:
The study explores the use of a thiamine antagonist called benfo-oxythiamine (B-OT) as a radiosensitizer to enhance the effectiveness of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) in a patient with treatment-refractory metastatic prostate cancer.

Research objectives and hypotheses:
The researchers hypothesized that combining B-OT with PRLT could reduce radiation resistance and achieve better therapeutic efficacy in the patient, who had progressed on all standard-of-care therapies as well as previous PRLT.

Methodology:
The patient received 177Lu-PRLT combined with the radiosensitizer B-OT (B-OT-PRLT) after failing all other treatments, including 177Lu-PRLT and TANDEM-PRLT (177Lu-PSMA/225Ac-PSMA).

Results and findings:
The patient showed a significant decline in prostate-specific antigen (PSA) levels and partial regression of metastases after just one cycle of B-OT-PRLT, despite having experienced massive disease progression before the start of this treatment. The combination of 177Lu-PSMA and B-OT was well-tolerated, and the patient reported significant improvement in clinical symptoms and general condition.

Discussion and interpretation:
The researchers suggest that the inhibition of transketolase enzymes by B-OT disrupts DNA synthesis and repair, thereby enhancing the effects of radiation-induced DNA damage caused by PRLT. This approach appears to have overcome the patient's radiation resistance.

Contributions to the field:
This is the first reported case of combining B-OT with PRLT, providing initial evidence that this combination could be a safe and effective strategy for treating heavily pretreated patients with radiation-refractory metastatic prostate cancer.

Achievements and significance:
The exceptional response observed in this treatment-refractory patient is very encouraging and supports the potential of B-OT as a radiosensitizer to improve the efficacy of PRLT.

Limitations and future work:
The study is limited to a single case report. The researchers plan to conduct a phase 1b/2 clinical study to further evaluate the safety, tolerability, and efficacy of B-OT as a radiosensitizer when used in combination with various radioligand therapies. 

Future Plans

According to the paper, there are plans for a phase 1b/2 clinical trial to evaluate B-OT as a radiosensitizer. Here are the specified details:

Trial Design:
- Type: Phase 1b/2 open-label, single-center study
- Structure: Will include both:
  * Dose-escalation phase
  * Dose-expansion phase

Key Goals:
- Evaluate safety
- Assess tolerability
- Determine efficacy of B-OT as a radiosensitizer
- Determine optimal dosing regimen for B-OT when combined with radioligand therapies

Context for Trial Design:
1. Safety Data Available:
- Phase I study with healthy volunteers showed:
  * 5 mg daily dose over 7 days was well-tolerated
  * This was higher than the 3 mg/5 days used in this case report

2. Potential for Dose Optimization:
- Since the patient eventually progressed on B-OT-PRLT
- The daily dose and treatment duration could potentially be increased based on Phase I safety data

This appears to be in planning stages and the paper suggests readers should await the formal trial for more comprehensive evaluation of this combination therapy.