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The Frontier Edge: New Appreciation of Triple Negative Disease – A Review (Part 2)

Epothilone Therapy

Epothilones are microtubule-stabilizing agents, but they target mitotic tubules in a different location than taxanes, with several advantages over the taxanes: unlike taxanes, epothilones appear to avoid developing resistance, being less sensitive than paclitaxel to multidrug-resistant proteins, and do not require steroid pretreatment. Furthermore, epothilones have gained a reputation of benefit in difficult-to-treat breast cancers such as metastatic patients who experience disease progression on anthracycline, taxane, and capecitabine (Xeloda) chemotherapy. One epothilone, ixabepilone (Ixempra) has just (10/16/07) obtained FDA approval, under priority review, and is already available for deployment, approved for treatment via intravenous infusion, either as monotherapy or in combination with capecitabine (Xeloda), of women with metastatic or locally advanced treatment-resistant breast cancer, including tumors  resistant or refractory to an anthracycline, a taxane or capecitabine. Craig Bunnell[55] at Dana-Farber and colleagues at MD Anderson conducted a Phase I/II trial of an ixabepilone + capecitabine combination regimen in metastatic patients previously treated with a taxane and an anthracycline, 44% of whom were triple negative, finding the combination synergistic and with an overall response rate of 30%, and with manageable toxicity.


Based on these and other promising clinical results, one BMS-sponsored multicenter clinical trial of ixabepilone + bevacizumab   (IXA + BEV) is actively recruiting, and another under Ellen Chuang[56] at Weill Medical College (Cornell) is recruiting for a trial of IXA + Doxil (ixabepilone + doxorubicin HCl liposome) in a variety of cancers including in MBC with patients previously treated with a taxane and a platinum agent.  And BMS is conducting a soon to recruit study of ixabepilone plus capecitabine or docetaxel plus capecitabine in metastatic breast cancer[57] which although not triple negative-specific, is designed to explicitly track triple-negative and non-triple-negative (NTN) subjects; given the recent approval of  

I should note here one caution about now-available ixabepilone (Ixempra) that is not highlighted in the official labeling, and that is the potential adverse interaction with certain natural agents, including St. John's Wort, chamomile, sage, licorice extract, the soybean components daidzein and genistein, grapefruit juice, and possibly also EPO (Evening Primrose Oil) / Borage (seed) Oil, and – as opposed to just these natural agents - the widely used pharmaceutical atorvastatin (Lipitor) .  The reason for this caution against coadministration of ixabepilone (Ixempra)  with any of these agents, natural and pharmaceutical, is that all of these agents are potent CYP3A4-inhibitors, and the metabolism of ixabepilone (Ixempra) is dependent on the CYP3A4 hepatic enzyme, part of what's called the P450 Cytochrome system. 


Metronomic Chemotherapy
There are several other options for triple negative therapy, and one of the more interesting  outside of clinical trials is from Robert Livingston[58], chair until this year of the Breast Cancer Committee of SWOG (Southwest Oncology Group) at the Arizona Cancer Center, who uses a base of metronomic therapy of lose-dose AC (using continuous daily oral cyclophosphamide (Cytoxan)) with G-CSF support followed by weekly paclitaxel in order to leverage antiangiogenic activity given the critical role of angiogenesis in triple negative disease, adding other chemotherapeutic agents to this base as needed, including the possibility of an added platinum or an antitubulin combination such as a nab-paclitaxel (Abraxane) and vinorelbine (Navelbine) regimen (Robert Livingston is the "father" of metronomic therapy in breast cancer, which leverages low-dose frequent or continuous schedules of oncotherapy to both induce angiogenic inhibition and to avoid the potential for tumor regrowth during the traditional chemotherapy breaks or rest periods, also reducing toxicity, and Dr. Livingston appropriately received a piano metronome for his 25 year service in the field from SWOG).  Paul Walker at East Carolina University is conducting a Phase II clinical trial of a neoadjuvant metronomic chemotherapy for triple negative disease[59], where women with a diagnosed triple-negative disease, confirmed on a core biopsy and larger than 2 cm, will be treated neoadjuvantly with the what is now come to be called, appropriately, the Livingston metronomic regimen of 12 weeks of weekly doxorubicin 24 mg/m2 and daily oral cyclophosphamide 60 mg/m2 followed by 12 successive weeks of paclitaxel (Taxol) 80 mg/m2 plus carboplatin.  


PARP Inhibitors

As I noted briefly above, PARP inhibitor biological  (non-chemotherapeutic) therapy is another genotoxic, DNA-damaging intervention of considerable potential benefit in the treatment of triple negative disease. PARP1

(poly (ADP-ribose) polymerase-1) is a nuclear enzyme that is involved in repairing DNA damage (called base excision repair), mediating cell death (apoptosis) and necrosis, and regulating immune response. PARP activation occurs when cells are damaged in instances such as during chemotherapy and  radiotherapy, and also in non-treatment events such as stroke, head trauma and heart ischemia.  The goal of targeting PARP is to prevent tumor cells from repairing DNA themselves and developing drug resistance, which may make them more sensitive to cancer therapies. In preclinical testing, PARP inhibitors have demonstrated the ability to increase the effect of various chemotherapeutic agents (e.g., DNA topoisomerase inhibitors II like the anthracyclines, or  cisplatin), as well as radiation therapy, against a broad spectrum of tumors.  Given that DNA is under constant attack from endogenous toxins, such as free radicals generated by cellular metabolism and exogenous toxins, including many carcinogens, it isn't surprising that cells have evolved and developed multiple mechanisms to ensure DNA integrity, with each DNA repair mechanism correcting a different subset of lesions. The PARP-1 nuclear enzyme addresses and repairs certain types of DNA damage in lesions, and so PARP inhibitors are essentially deployed to block the repair of such DNA damage by PARP1 and hence induce tumor cell death.


Because many chemotherapeutic agents in common use are known to, or likely to, induce double-strand breaks (DSBs), and because this DNA-damaging activity of genotoxic chemotherapeutic agents converges with the ultimate goal of PARP inhibitors to block such damage and hence allow the DNA damage to go unrepaired in tumor cells, there is a natural and molecular plausibility to a synergism between genotoxic chemotherapies and PARP inhibitory agents, and to the strategy I might call PARP-inhibitor sensitization of genotoxic chemotherapy. This use of PARP-1 inhibitors in combination with standard chemotherapeutic agents also seems attractive from the point of view that sensitizing tumor cells to cytotoxic agents one might enable lower chemotherapy dosing while maintaining the same relative efficacy, and hence reducing overall treatment toxicity.

There is therefore plausible early evidence that defective DNA damage repair may make BRCA1-deficient cancer cells more sensitive to DNA damaging agents, and the  benefit may not just be limited to such BRCA-1 deficient tumor cells: the NIDDKD (National Institute of Diabetes and Digestive and Kidney Diseases) team under Chu-Xia Deng[60] found that PARP-1 inhibitors can inhibit breast cancer cells irrespective of their BRCA1 and ER status.


However, as noted also by Dr. Tito Fojo[61] with the Center for Cancer Research at NCI, this therapeutic strategy of  genotoxic chemotherapy + PARP-Inhibition has the potential to enhance chemotherapy toxicity, and possibly also the incidence of secondary malignancies, especially leukemias. Nonetheless, this potential for the emergence of higher toxicities and/or incidence of secondary leukemias  remains only a theoretical concern and no robust clinical data has as yet provides confirmation or disconfirmation, to me somewhat reassuring perhaps given the deployment of PARP inhibition across an extraordinarily wide spectrum of disorders (cardiomyopathy and myocardial injury, stroke, neurotrauma, arthritis, inflammatory bowel disease, allergic encephalomyelitis, multiple sclerosis, diabetes, HIV infection, as well as various cancers, among many other conditions).

PARP-1 inhibitors also are attractive agents based on what seems to be not only few side effects but also a protective effect in normal tissue. Indeed, reports from clinical trials using PARP-1 inhibitors have successfully completed phase I studies and entered phase II studies for various ischemic disorders. Furthermore, PARP-1 inhibitors seem to protect against the nephrotoxicity of cisplatin[62] and the cardiotoxicity of doxorubicin[63].

Yoon-Sim Yap[64] at Royal Marsden Hospital and colleagues tested AZD2281
(formerly called KU-0059436), with encouraging anti-tumor activity reported in early results presented at ASCO 2007 (the presentation received an ASCO merit award), and minimal toxicity (the target dose being 600 mg bid continuously); toxicities including low grade (1 – 2) fatigue, anorexia, constipation and diarrhea, and some grade 4 platelet cell reduction.  This study is part of the ICEBERG 1 trial, a collaborative effort with the Royal Marsden Hospital and Netherlands Cancer Institute (NKI).  And although most attention has focused on this ICEBERG 1 AstraZenica trial of the AZD2281 / KU-0059436) PARP inhibitor, another equally important trial is the Phase I study of AZD0530 for Src inhibition[65], also reported at ASCO 2007; the Src kinases play an important role in cancer growth, and cell proliferation, focal adhesion, invasion, metastasis (through motility), and apoptosis, so Src inhibition is thought to be critical in the delay of cancer progression, and more critically may assist in the treatment of various metastases including bone while, like other PARP inhibitors, synergizing the antitumor activity of chemotherapy.

 mTOR Inhibitors

I have long been a strong advocate of the potential benefit of mTOR (mammalian target of rapamycin) inhibition in the treatment of breast cancer, and am heartened to finally observe that mTOR inhibitors are finally being explored in this capacity, including for the treatment of triple negative disease. I'll note here that the mTOR kinase is downstream of the PI3K/Akt pathway, an important regulator of cell proliferation and survival, and to also affect VEGF production at multiple levels, and breast cancers with mTOR overexpression showed a three times greater risk for disease recurrence[67] and the mTOR inhibitor rapamycin was found to potentiate the cytotoxicity of selected chemotherapeutic agents, including paclitaxel (Taxol), carboplatin, and vinorelbine (Navelbine), and dramatically enhance paclitaxel- and carboplatin-induced apoptosis[68,69], as well as exerting antitumor activity in breast cancer via antiangiogenesis as demonstrated with findings on temsirolimus (Torisel) [70], an mTOR inhibitor which has already shown dramatic benefit in RCC (renal cell carcinoma).  Recent results of mTOR inhibition in breast cancer are highly promising[71–74]. There has also been promising activity with partial responses observed both in patients with visceral-dominant and soft tissue-dominant breast cancer metastases[75].

I note also here that the natural agent curcumin curcumin's anticancer activity appears to operate primarily by blocking mTOR-mediated signaling pathways in the tumor cells, also induced apoptosis and inhibiting the basal or type I insulin-like growth factor-induced motility of the cells, also inhibiting at high concentrations the phosphorylation of Akt in tumor cells[76-78]. Also intriguing in this connection is the recent finding that mTOR suppression may be associated with antitumor actions of caloric restriction[79], which hints that caloric restriction may be of special benefit in potentially mTOR-dependent and/or sensitive breast carcinoma such as triple negative disease. This would also help account for the disproportionately large benefit in terms of degree of recurrence risk reduction engendered by even very modest caloric restriction and weight control in breast cancer patients, a theme underlined in Carol Fabian's excellent presentation on Preventing Breast Cancer – What's New

[click on link to download as pdf] at the recent 2007 Controversies in Breast Cancer conference in NY.


In terms of clinical trials of mTOR inhibition in breast cancer, Ana Gonzalez-Angulo[80] at MD Anderson is examining in a clinical trial the use of an mTOR inhibitor (RAD001) + a taxane (paclitaxel) as neoadjuvant chemotherapy compared to the same taxane + FEC chemotherapy.


Before concluding this section on mTOR inhibitors, I note that forthcoming research from Ryan Dowling at McGill University has found that the anti-diabetes agent metformin (Glucophage) inhibits mTOR-dependent translation initiation in breast cancer cells (publication pending, November issue of the Cancer Research journal), building on and confirming earlier results from Dowling's colleague Mahvash Zakikhani[81] that metformin-induced growth inhibition was associated  with decreased mammalian target of rapamycin.  This is molecularly persuasive given that insulin and insulin-like growth factors (IGF) stimulate proliferation  in many cell types, and suggests antineoplastic activity by metformin via growth  inhibition of breast cancer epithelial cells; indeed high mammographic breast density known  to predict increased breast cancer risk is associated  with higher concentrations of circulating IGF-I[82,83] and insulin-like growth factor-I (IGF-I), which also plays a  critical role in carcinogenesis and tumorigenesis[84]. These considerations would help to account the antitumor effect of caloric restriction via mTOR inhibition, as caloric restriction may involve underlying insulin and IGF pathways, and suggest that both caloric restriction and glucose / insulin control may play specific beneficial functions in triple negative disease via the new-found contribution of mTOR inhibition, and add another item of defense to the growing arsenal deployable against triple negative breast carcinoma. 

Summary of Triple Negative Disease Therapy
It should be clear from the above that there are now, and more soon emerging, an extraordinarily wide range of significantly effective therapeutic interventions for the treatment of triple negative disease.  These include:


Triple-Negative Sensitive Chemotherapy

Cyclophosphamide (Cytoxan) [genotoxic]

Platinum Agents: Carboplatin (Paraplatin), Cisplatin (Platinol) [genotoxic]

Anthracyclines: Doxorubicin (Adriamycin), Epirubicin (Ellence) [genotoxic]

Taxanes (Cremophor-based): Paclitaxel (Taxol), Docetaxel (Taxotere)

Nanoparticle Albumin-bound Paclitaxel: nab-paclitaxel (Abraxane)

Mitomycin C (MTC / Mitomycin / Mutamycin) [genotoxic]

HDCT (High-Dose Chemotherapy) [genotoxicity dependent on component agents]

Metronomic Chemotherapy [genotoxicity dependent on component agents]

Epothilone Therapy: Ixabepilone (Ixempra)


Triple-Negative Sensitive Genotoxic Radiotherapy

Triple-Negative Sensitive Genotoxic Biological Therapy
PARP Inhibitors

HSP90 (Heat Shock Protein-90)

Anti-VEGF / Antiangiogenic Chemobiotherapy

Bevacizumab (Avastin)

EGFR-Targeted Therapies
Cetuximab (Erbitux)

Sunitinib (Sutent)
Dasatinib (Sprycel)

mTOR Inhibitors

A Note of this Contribution (Part 2)

Although I have not included source references directly in this posting to avoid excessive technical "weight", the reference numbers are included – in the form of a bracketed [] number or numbers in the text – and anyone interested can access the sources themselves in the technical version of this posting available online as Issue 3 of my Breast Cancer Watch Digest newsletter, where the references are also hyperlinked to the original sources.  That version also contains some additional tutorial-type material on DNA damage and PARP inhibitors, and briefly describes the methodology of the review, while this special invited presentation for the No Surrender forum has additional material relating to recent conference discussions plus some hints at findings to be reported at the upcoming SABCS 2007 this December.

Constantine Kaniklidis

Medical Researcher

Breast Cancer Watch





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