The Promise of Combining Inhibition of PI3K and PARP as Cancer Therapy

Rehman, Farah L.; Lord, Christopher J.; Ashworth, Alan

doi:10.1158/2159-8290.cd-12-0433

Cited by 41 publications

(29 citation statements)

References 12 publications

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“…PARP inhibitors have shown clinically significant activity in BRCA1 - or BRCA2 -mutated ovarian cancers (later-stage studies in BRCA -deficient TNBC patients are ongoing), due to a synthetic lethal mechanism in cells deficient in homologous combination-mediated DNA repair (Lord and Ashworth, 2016). Combinations of PI3K/mTOR pathway inhibitors and PARP inhibitors have also shown promising activity in prostate, ovarian and SCLC models (Cardnell et al, 2013; González-Billalabeitia et al, 2014; Rehman et al, 2012; Wang et al, 2016). Once again, results from an early clinical trial with buparlisib and olaparib suggest that toxicity will be a formidable obstacle to attaining the drug exposures needed to achieve an optimal therapeutic effect with this drug combination (Matulonis et al, 2016).…”

Section: Therapeutic Targeting Of the Pi3k Pathway In Cancermentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,886

1,658

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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Section: Therapeutic Targeting Of the Pi3k Pathway In Cancermentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,886

1,658

View full text Add to dashboard Cite

show abstract

“…However, neoadjuvant chemotherapy has much less impact in luminal breast cancers, and it has almost no activity in the luminal A subtype [4]. Finally, clinical benefit from HER2-targeting agents is largely restricted to women with HER2-enriched cancers, and there is the sense that inhibitors of poly(ADP-ribose) polymerase (PARP), which are very active in ovarian cancers that contain inactivating BRCA1 or BRCA2 mutations, may also be active in basal-like breast cancers, particularly if they are combined with other targeted agents [13].…”

Section: Key Pointsmentioning

confidence: 99%

Genetic subtypes of invasive bladder cancer

McConkey

Choi

Dinney

2015

Current Opinion in Urology

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Like their breast cancer counterparts, basal bladder cancers are characterized by poor clinical outcomes in the absence of effective systemic therapy, but a large fraction of them do respond to neoadjuvant chemotherapy, suggesting that the tumors should be managed aggressively. On the contrary, tumors that belong to the 'p53-like' subtype tend to be chemoresistant, so patients with these tumors should probably be managed differently. It seems likely that prospective identification of tumor intrinsic subtype membership could complement the use of DNA-based biomarkers to identify the groups of patients who will benefit the most from chemotherapy and targeted agents.

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“…Indeed, some promising combination treatments with PI3K inhibitors have recently been reported, such as with inhibitors of PARP (reviewed in Ref. [67]) or CDK4/6 (Ref. [68]) in breast cancer.…”

Section: Resultsmentioning

confidence: 99%

Molecules in medicine mini-review: isoforms of PI3K in biology and disease

2015

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The PI3K lipid kinases are involved in signal transduction and intracellular vesicular traffic, endowing these enzymes with multiple cellular functions and important roles in normal physiology and disease. In this mini-review, we aim to distil from the vast PI3K literature the key relevant concepts for successful targeting of this pathway in disease. Of the eight isoforms of PI3K, the class I PI3Ks have been implicated in the aetiology and maintenance of various diseases, most prominently cancer, overgrowth syndromes, thrombosis, inflammation and autoimmunity, with emerging potential roles in metabolic, cardiovascular and other disorders. The development of class I PI3K inhibitors, mainly for use in cancer and inflammatory disorders, is a very active area of drug development. In 2014, an inhibitor of the p110δ isoform of PI3K was approved for the treatment of some human B-cell malignancies. The key therapeutic indications of targeting each class I PI3K isoform are summarized and discussed.

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The Promise of Combining Inhibition of PI3K and PARP as Cancer Therapy

Cited by 41 publications

References 12 publications

The PI3K Pathway in Human Disease

The PI3K Pathway in Human Disease

Genetic subtypes of invasive bladder cancer

Molecules in medicine mini-review: isoforms of PI3K in biology and disease

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