# Effects of Arginine Depletion Combined with Platinum-Taxane Chemotherapy in Aggressive Variant Prostate Cancers (AVPC)

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $604,748

## Abstract

PROJECT SUMMARY/ABSTRACT
 Androgen indifferent prostate cancers account for a large proportion of the disease lethality and have
limited therapy options, partly due to the lack of identifying biomarkers. To address the unmet need of
developing effective therapies for this subset, we defined the aggressive variant prostate cancers (AVPC)
criteria. Through a series of prospective trials and studies in mice, we showed that the AVPC criteria can enrich
for prostate cancers that respond poorly to androgen inhibition and benefit from adding carboplatin to
cabazitaxel. In recent trials we examined the contribution of PARP inhibitor maintenance, and of anti-PD1
inhibition to the chemotherapy backbone in men with AVPC. Early data show meaningful improvements in
outcomes with these additions, but many men with AVPC are still progressing rapidly. Our overall goal is to
arrive at rational, biologically-based combination therapies that effectively treat the AVPC.
 The analysis of samples from our trial participants, and preclinical studies, converge on altered arginine
metabolism as a key metabolic pathway in androgen-indifferent prostate cancer biology. We also found
evidence of argininosuccinate synthase 1 (ASS1) silencing with platinum chemotherapy in AVPC cell lines
and patient samples. ASS1 deficiency renders cells dependent on extracellular arginine, and thus sensitive to
arginine depletion with agents such as PEGylated arginine deiminase (ADI-PEG20). ADI-PEG20 depletes
serum arginine levels, has activity in several malignancies (alone and in combination with chemotherapy), and
has immunomodulatory effects. However, the effects of serum arginine depletion on intratumoral metabolite
levels in patients are unknown, and its effects on the human immune tumor microenvironment (TME) remain
poorly understood. We hypothesize that the addition of ADI-PEG20 will improve the efficacy of
carboplatin+cabazitaxel by modifying intratumoral arginine metabolism and immune profiles in the
AVPC TME.
 In AIM 1, we will conduct a phase I/II dose escalation trial to identify the optimal dose (in terms of safety and
efficacy) of ADI-PEG20 to combine with carboplatin+cabazitaxel in men with AVPC. In AIM 2, peripheral blood
and metastatic tumor biopsies obtained from trial participants at baseline, after 1 and after 6 cycles of treatment,
and at parallel time-points in PDX and syngeneic mouse models, will be used to measure associations between:
(a) serum levels of arginine and citrulline, (b) intratumoral levels of arginine, (c) ASS1 expression, and (d) the
expression of other arginine metabolism enzymes, and (e) outcomes. In AIM 3 we will examine the effects of
treatment on immune profiles and immune cell distribution within the TME.
 Our studies will provide a comprehensive evaluation of the effects of serum arginine depletion on the immune
and non-immune AVPC TME, shed light on the mechanisms of synergy between ADI-PEG20 and cytotoxic
chemotherapy, and ultimately, serve to ...

## Key facts

- **NIH application ID:** 10932183
- **Project number:** 5R01CA283402-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Ana Aparicio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $604,748
- **Award type:** 5
- **Project period:** 2023-09-21 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932183

## Citation

> US National Institutes of Health, RePORTER application 10932183, Effects of Arginine Depletion Combined with Platinum-Taxane Chemotherapy in Aggressive Variant Prostate Cancers (AVPC) (5R01CA283402-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10932183. Licensed CC0.

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