# Cell Cycle Blockade and Therapeutic Sensitization

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,000

## Abstract

Cisplatin and carboplatin (Pt) are used heavily in the clinic against a variety of cancers, such as those of
ovarian, non-small cell lung (NSCLC), testicular, head & neck, and bladder origin. These drugs demonstrate
good activity, but in most cases, the activity is short-lived as tumors become desensitized by the onset of
resistance. Several options are available to sensitize tumor cells to platinum-based therapy. Since Pt drugs
interact with DNA to form DNA adducts as a mechanism of their action, inhibition of DNA repair can make
tumor cells highly sensitive through persistence of the DNA adduct. Repair of these adducts by nucleotide
excision repair (NER) in testicular cancers is low, which makes these cancers highly sensitive to Pt drugs and
leads to about 90% cure rate. Recent data suggests that repair of these adducts is complex, and involves
NER-mediated incisions that induce double strand breaks as intermediates, which are then repaired by
homologous recombination (HR). The base excision repair (BER) pathway has also been implicated in cisplatin
repair. Interestingly, the spectrum of Pt activity in the clinic has broadened to include triple-negative breast
cancers that harbor BRCA1 mutation or low BRCA1 expression (BRCAness tumors). High sensitivity has also
been observed in hereditary or low-expressing BRCA1 ovarian cancers. Sensitization from loss of BRCA1 is
due to resultant HR defect, which when combined with inhibition of poly-(ADP-ribose)-polymerase (PARP) in
the BER pathway by olaparib produces synthetic lethality. Thus, olaparib further augments Pt sensitivity in
tumors with the BRCAness phenotype. This sensitization, however, is limited to the small number of BRCA1
patients, but in our proposal we will test the hypothesis that small molecules inducing cell cycle blockade will
suppress BRCA1 expression in BRCA1-proficient ovarian and breast cancers to enhance tumor cell sensitivity
to Pt drugs and PARP inhibitors. We will address this hypothesis through three specific aims: 1) Establish the
relationship between cell cycle blockade and BRCA1 expression and delineate the mechanism of cell cycle
blockade causing BRCA1 suppression; 2) Define downstream mechanisms downregulating BRCA1 as a result
of cell cycle blockade; and 3) Identify rational combinations for synergistic activity and demonstrate proof-of-
concept in xenograft/PDX systems. Several agents are reported independently to induce cell cycle arrest and
we will prospectively establish the novel relationship with BRCA1 suppression utilizing pharmacologic tools to
define antitumor activity, biochemical and molecular tools to define the underlying basis of cell cycle blockade
and of BRCA1 suppression, and use the Bliss and Chou-Talalay mathematical models to identify synergistic
combinations of cisplatin and olaparib with an optimal inducer of BRCAness. This project has the potential to
sensitize cisplatin refractory cancers and also broaden the cancer base that could be treated r...

## Key facts

- **NIH application ID:** 9931050
- **Project number:** 5R01CA211975-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** ZAHID H SIDDIK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2017-07-06 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931050

## Citation

> US National Institutes of Health, RePORTER application 9931050, Cell Cycle Blockade and Therapeutic Sensitization (5R01CA211975-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9931050. Licensed CC0.

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